Pyrimidoheterocyclic compounds and application thereof

ABSTRACT

A class of pyrimidoheterocyclic compounds, and specifically disclosed is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.

This application claims the priority of:

CN202010172140.2, filed on Mar. 12, 2020;CN202010323035.4, filed on Apr. 22, 2020;CN202010953203.8, filed on Sep. 11, 2020;CN202011593642.9, filed on Dec. 29, 2020.

FIELD OF THE INVENTION

The present disclosure relates to a class of pyrimidoheterocycliccompounds, specifically to a compound represented by formula (III) or apharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

RAS oncogene mutations are the most common activating mutations in humancancers, occurring in 30% of human tumors. The RAS gene family includesthree subtypes (KRAS, HRAS and NRAS), of which 85% of RAS-driven cancersare caused by mutations in the KRAS subtype. KRAS mutations are commonlyfound in solid tumors, such as lung adenocarcinoma, pancreatic ductalcarcinoma and colorectal cancer, etc. In KRAS mutated tumors, 80% ofoncogenic mutations occur at codon 12, and the most common mutationsinclude: p.G12D (41%), p.G12V (28%) and p.G12C (14%).

The full name of KRAS gene is Kirsten rat sarcoma viraloncogene homolog.KRAS plays a pivotal role in the signaling regulation of cell growth.The upstream cell surface receptors such as EGFR (ErbB1), HER2 (ErbB2),ErbB3, and ErbB4, after receiving external signals, will transmit thesignal to downstream through the RAS protein. When the KRAS protein isnot activated, it binds tightly to GDP (guanosine diphosphate). Afterbeing activated by guanosine exchange factor such as SOS1, the KRASprotein binds to GTP (guanosine triphosphate) and becomes a kinaseactive state. After mutation, KRAS gene can independently transmitsignals for growth and proliferation to downstream pathways independentof upstream growth factor receptor signals, causing uncontrolled cellgrowth and tumor progression. Meanwhile, whether KRAS gene has mutationsor not is also an important indicator of tumor prognosis.

Although KRAS is the first oncogene to be discovered, it has long beenconsidered an undruggable target. Until 2019, Amgen and MiratiTherapeutics successively published the clinical research results oftheir small molecule KRAS inhibitors AMG510 and MRTX849, which confirmedthe clinical effectiveness of KRAS inhibitors in the clinical treatmentof tumors for the first time. Both AMG 510 and MRTX849 are irreversiblesmall molecule inhibitors that inhibit KRAS activity by formingirreversible covalent bonds with cysteine residues of KRAS G12C mutantprotein.

Statistical results show that 12-36% of lung adenocarcinoma is driven byKRAS mutations; 27-56% of colon cancer is driven by KRAS; and 90% ofpancreatic cancer, 21% of endometrial cancer, and 12-36% of lungadenocarcinoma are driven by KRAS, which indicate that the patientpopulation is huge. In KRAS gene mutations, 97% of the mutations occurin amino acid residues at position 12 or 13, wherein G12D, G12V and G13Dmutations have poor druggability, and KRAS (G12C) mutation in whichglycine at position 12 is replaced by cysteine provides a good directionfor the development of covalent inhibitors.

SUMMARY OF THE INVENTION

The present disclosure provides a compound represented by formula (III)or a pharmaceutically acceptable salt thereof,

wherein

T₁ is selected from O and N;

R₁ is selected from C₆₋₁₀ aryl and 5- to 10-membered heteroaryl, whereinthe C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with 1, 2, 3, 4 or 5 R_(a);

when T₁ is O, R₂ is not present;

when T₁ is N, R₂ is selected from H, C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and—S(═O)₂—C₁₋₃ alkyl, wherein the C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and—S(═O)₂—C₁₋₃ alkyl are optionally substituted with 1, 2 or 3 R_(b);

R₃ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1, 2 or 3 R_(c);

R₄ is selected from H and C₁₋₃ alkyl, wherein the C₁₋₃ alkyl isoptionally substituted with 1, 2 or 3 R_(d);

R₅, R₆ and R₇ are each independently selected from H, F, Cl, Br, I, andC₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with 1, 2or 3 F;

R₈ is selected from H and CH₃;

R_(a) is each independently selected from F, Cl, Br, I, OH, NH₂, CN,C₁₋₃ alkyl, C₁₋₃ alkoxy, C₂₋₃ alkynyl and C₂₋₃ alkenyl, wherein the C₁₋₃alkyl, C₁₋₃ alkoxy, C₂₋₃ alkynyl and C₂₋₃ alkenyl are optionallysubstituted with 1, 2 or 3 F;

R_(b) is each independently selected from F, Cl, Br, I, OH and NH₂;

R_(c) is each independently selected from 4- to 8-memberedheterocycloalkyl, wherein the 4- to 8-membered heterocycloalkyl isoptionally substituted with 1, 2 or 3 R;

R_(d) is each independently selected from F, Cl, Br, I, OH, NH₂ and CN;

R is each independently selected from H, F, Cl, Br, OH, CN, C₁₋₃ alkyl,C₁₋₃ alkoxy and —C₁₋₃ alkyl-O—CO—C₁₋₃ alkylamino;

provided that when R₁ is naphthyl, the naphthyl is optionallysubstituted with F, Cl, Br, OH, NH₂, CF₃, CH₂CH₃ and —C≡CH, and R₅, R₆and R₇ are each independently H.

In some embodiments of the present disclosure, the above R_(a) is eachindependently selected from F, Cl, Br, I, OH, NH₂, CN, CH₃, CH₂CH₃,OCH₃, OCH₂CH₃, —CH═CH₂, —CH₂—CH═CH₂ and —C≡CH, wherein the CH₃, CH₂CH₃,OCH₃, OCH₂CH₃, —CH═CH₂, —CH₂—CH═CH₂ and —C≡CH are optionally substitutedwith 1, 2 or 3 F, and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R_(a) is eachindependently selected from F, OH, NH₂, CH₃, CF₃, CH₂CH₃ and —C≡CH, andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₁ is selectedfrom phenyl, naphthyl, indolyl and indazolyl, wherein the phenyl,naphthyl, indolyl and indazolyl are optionally substituted with 1, 2 or3 R_(a), and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₁ is selectedfrom

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is selectedfrom H, CH₃, CH₂CH₃ and CH(CH₃)₂, wherein the CH₃, CH₂CH₃ and CH(CH₃)₂are optionally substituted with 1, 2 or 3 R_(b), and other variables areas defined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is selectedfrom H and CH₃, and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R is eachindependently selected from H, F, Cl, Br, OH, CN, CH₃, CH₂CH₃, CH₂CF₃,OCH₃, OCF₃ and

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R_(c) isselected from tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl, whereinthe tetrahydropyrrolyl and hexahydro-1H-pyrrolizinyl are optionallysubstituted with 1, 2 or 3 R, and other variables are as defined in thisdisclosure.

In some embodiments of the present disclosure, the above R_(c) isselected from

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R_(c) isselected from

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is CH₃,wherein the CH₃ is optionally substituted with 1, 2 or 3 R_(c), andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is selectedfrom

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is selectedfrom

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is selectedfrom H and CH₃, wherein the CH₃ is optionally substituted with 1, 2 or 3R_(d), and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is selectedfrom H, CH₃ and CH₂CN, and other variables are as defined in thisdisclosure.

The present disclosure provides a compound represented by formula (III)or a pharmaceutically acceptable salt thereof,

wherein

T₁ is selected from O and N;

R₁ is selected from phenyl, naphthyl and indazolyl, wherein the phenyl,naphthyl and indazolyl are optionally substituted with 1, 2, 3, 4 or 5R_(a);

when T₁ is O, R₂ is not present;

when T₁ is N, R₂ is selected from H, C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and—S(═O)₂—C₁₋₃ alkyl, wherein the C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and—S(═O)₂—C₁₋₃ alkyl are optionally substituted with 1, 2 or 3 R_(b);

R₃ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1, 2 or 3 R_(c);

R₄ is selected from H and C₁₋₃ alkyl, wherein the C₁₋₃ alkyl isoptionally substituted with 1, 2 or 3 R_(d);

R₅, R₆ and R₇ are each independently selected from H, F, Cl, Br, I, OHand NH₂;

R₈ is selected from H and CH₃;

R_(a) is each independently selected from F, Cl, Br, I, OH, NH₂, CN,CH₃, CF₃ and OCH₃;

R_(b) is each independently selected from F, Cl, Br, I, OH and NH₂;

R_(c) is each independently selected from tetrahydropyrrolyl andhexahydro-1H-pyrrolizinyl, wherein the tetrahydropyrrolyl andhexahydro-1H-pyrrolizinyl are substituted with 1, 2 or 3 R;

R_(d) is each independently selected from F, Cl, Br, I, OH, NH₂ and CN;

R is each independently selected from H, F, Cl, Br and CH₃.

In some embodiments of the present disclosure, disclosed is the abovecompound or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from,

wherein

R₄ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1, 2 or 3 R_(d);

T₁, R₁, R₂, R₃, R₅, R₆, R₇ and R_(d) are as defined in this disclosure;

the carbon atom with “*” is a chiral carbon atom, which exists in theform of (R) or (S) single enantiomer or is enriched in one enantiomer.

In some embodiments of the present disclosure, the above R₁ is selectedfrom phenyl, naphthyl and

wherein the phenyl, naphthyl and

are optionally substituted with 1, 2 or 3 R_(a), and other variables areas defined in this disclosure.

In some embodiments of the present disclosure, the above R₁ is selectedfrom

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is selectedfrom H, CH₃, CH₂CH₃ and CH(CH₃)₂, wherein the CH₃, CH₂CH₃ and CH(CH₃)₂are optionally substituted with 1, 2 or 3 R_(b), and other variables areas defined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is selectedfrom H and CH₃, and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R_(c) isselected from

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R_(c) isselected from

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is CH₃,wherein the CH₃ is optionally substituted with 1, 2 or 3 R_(c), andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is selectedfrom

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is selectedfrom

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is selectedfrom H and CH₃, wherein the CH₃ is optionally substituted with 1, 2 or 3R_(d), and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is selectedfrom H, CH₃ and CH₂CN, and other variables are as defined in thisdisclosure.

The present disclosure provides a compound represented by formula (III)or a pharmaceutically acceptable salt thereof,

wherein

T₁ is selected from O and N;

R₁ is selected from phenyl, naphthyl and indazolyl, wherein the phenyl,naphthyl and indazolyl are optionally substituted with 1, 2, 3, 4 or 5R_(a);

when T₁ is O, R₂ is not present;

when T₁ is N, R₂ is selected from H, C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and—S(═O)₂—C₁₋₃ alkyl, wherein the C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and—S(═O)₂—C₁₋₃ alkyl are optionally substituted with 1, 2 or 3 R_(b);

R₃ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1, 2 or 3 R_(c);

R₄ is selected from H and C₁₋₃ alkyl, wherein the C₁₋₃ alkyl isoptionally substituted with 1, 2 or 3 R_(d);

R₅, R₆ and R₇ are each independently selected from H, F, Cl, Br, I, OHand NH₂;

R₈ is selected from H and CH₃;

R_(a) is each independently selected from F, Cl, Br, I, OH, NH₂, CN,CH₃, CF₃ and OCH₃;

R_(b) is each independently selected from F, Cl, Br, I, OH, NH₂ and CH₃;

R_(c) is each independently tetrahydropyrrolyl, wherein thetetrahydropyrrolyl is substituted with 1, 2 or 3 R;

R_(d) is each independently selected from F, Cl, Br, I, OH, NH₂ and CN;

R is each independently selected from F, Cl, Br and CH₃.

In some embodiments of the present disclosure, disclosed is the abovecompound or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from,

wherein T₁, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are as defined in thisdisclosure;

the carbon atom with “*” is a chiral carbon atom, which exists in theform of (R) or (S) single enantiomer or is enriched in one enantiomer.

In some embodiments of the present disclosure, the above R₁ is selectedfrom phenyl, naphthyl and

wherein the phenyl, naphthyl and

are optionally substituted with 1, 2 or 3 R_(a), and other variables areas defined in this disclosure.

In some embodiments of the present disclosure, the above R₁ is selectedfrom

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is selectedfrom H, CH₃, CH₂CH₃ and CH(CH₃)₂, wherein the CH₃, CH₂CH₃ and CH(CH₃)₂are optionally substituted with 1, 2 or 3 R_(b), and other variables areas defined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is selectedfrom H and CH₃, and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R_(c) is

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is CH₃,wherein the CH₃ is optionally substituted with 1, 2 or 3 R_(c), andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is CH₃,wherein the CH₃ is optionally substituted with 1, 2 or 3 R_(d), andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is CH₂CN,and other variables are as defined in this disclosure.

The present disclosure provides a compound represented by formula (II)or a pharmaceutically acceptable salt thereof,

wherein

T₁ is selected from O and N;

R₁ is selected from phenyl and naphthyl, wherein the phenyl and naphthylare optionally substituted with 1, 2 or 3 R_(a);

when T₁ is O, R₂ is not present;

when T₁ is N, R₂ is selected from C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and—S(═O)₂—C₁₋₃ alkyl, wherein the C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and—S(═O)₂—C₁₋₃ alkyl are optionally substituted with 1, 2 or 3 R_(b);

R₃ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1, 2 or 3 R_(c);

R₄ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1, 2 or 3 R_(d);

R₅, R₆ and R₇ are each independently selected from H, F, Cl, Br, I, OHand NH₂;

R_(a) is each independently selected from F, Cl, Br, I, OH, NH₂, CN, CH₃and OCH₃;

R_(b) is each independently selected from F, Cl, Br, I, OH, NH₂ and CH₃;

R_(c) is each independently tetrahydropyrrolyl, wherein thetetrahydropyrrolyl is substituted with 1, 2 or 3 R;

R_(d) is each independently selected from F, Cl, Br, I, OH, NH₂ and CN;

R is each independently selected from F, Cl, Br and CH₃;

the carbon atom with “*” is a chiral carbon atom, which exists in theform of (R) or (S) single enantiomer or is enriched in one enantiomer.

In some embodiments of the present disclosure, the above R₁ is naphthyl,wherein the naphthyl is optionally substituted with 1, 2 or 3 R_(a), andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₁ is selectedfrom

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is selectedfrom CH₃, CH₂CH₃ and CH(CH₃)₂, wherein the CH₃, CH₂CH₃ and CH(CH₃)₂ areoptionally substituted with 1, 2 or 3 R_(b), and other variables are asdefined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is CH₃, andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R_(c) is

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is CH₃,wherein the CH₃ is optionally substituted with 1, 2 or 3 R_(c), andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is CH₃,wherein the CH₃ is optionally substituted with 1, 2 or 3 R_(d), andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is CH₂CN,and other variables are as defined in this disclosure.

The present disclosure provides a compound represented by formula (I) ora pharmaceutically acceptable salt thereof,

wherein

R₁ is selected from phenyl and naphthyl, wherein the phenyl and naphthylare optionally substituted with 1, 2 or 3 R_(a);

R₂ is selected from C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and —S(═O)₂—C₁₋₃alkyl, wherein the C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and —S(═O)₂—C₁₋₃ alkylare optionally substituted with 1, 2 or 3 R_(b);

R₃ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1, 2 or 3 R_(c);

R₄ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1, 2 or 3 R_(d);

R₅, R₆ and R₇ are each independently selected from H, F, Cl, Br, I, OHand NH₂;

R_(a) and R_(b) are each independently selected from F, Cl, Br, I, OH,NH₂ and CH₃;

R_(c) is each independently tetrahydropyrrolyl, wherein thetetrahydropyrrolyl is substituted with 1, 2 or 3 R;

R_(d) is each independently selected from F, Cl, Br, I, OH, NH₂ and CN;

R is each independently selected from F, Cl, Br and CH₃;

the carbon atom with “*” is a chiral carbon atom, which exists in theform of (R) or (S) single enantiomer or is enriched in one enantiomer.

In some embodiments of the present disclosure, the above R₁ is naphthyl,and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₁ is

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is selectedfrom CH₃, CH₂CH₃ and CH(CH₃)₂, wherein the CH₃, CH₂CH₃ and CH(CH₃)₂ areoptionally substituted with 1, 2 or 3 R_(b), and other variables are asdefined in this disclosure.

In some embodiments of the present disclosure, the above R₂ is CH₃, andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R_(c) is

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is CH₃,wherein the CH₃ is optionally substituted with 1, 2 or 3 R_(c), andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₃ is

and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is CH₃,wherein the CH₃ is optionally substituted with 1, 2 or 3 R_(d), andother variables are as defined in this disclosure.

In some embodiments of the present disclosure, the above R₄ is CH₂CN,and other variables are as defined in this disclosure.

In some embodiments of the present disclosure, disclosed is the abovecompound or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from,

wherein R₁, R₅, and R_(c) are as defined in this disclosure;

R₄ is C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with1, 2 or 3 R_(d);

R_(d) is each independently selected from F, Cl, Br, I, OH, NH₂ and CN;

the carbon atom with “*” is a chiral carbon atom, which exists in theform of (R) or (S) single enantiomer or is enriched in one enantiomer.

In some embodiments of the present disclosure, disclosed is the abovecompound or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from:

wherein

R₁, R₂, R₄, R₅, R₆, R₇, R₈ and R are as defined in this disclosure.

The present disclosure also includes some embodiments obtained by anycombination of the above variables.

The present disclosure provides a compound of the following formula or apharmaceutically acceptable salt thereof,

In some embodiments of the present disclosure, disclosed is the abovecompound or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from,

In some embodiments of the present disclosure, disclosed is the abovecompound or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from,

The present disclosure also provides use of the above compound or apharmaceutically acceptable salt thereof in the manufacture of amedicament for treating diseases related to KRASG12C mutant protein.

Technical Effect

The compounds of the present disclosure have good cell proliferationinhibitory activity on KRASG12C-mutated MIA-PA-CA-2 cell line andNCI-H358 cells. The compounds of the present disclosure have goodstability in liver microsomes, hepatocytes, plasma and whole blood, aswell as good PK properties and significant anti-tumor effect.

Related Definitions

Unless otherwise specified, the following terms and phrases used hereinare intended to have the following meanings. A specific term or phraseshould not be considered indefinite or unclear in the absence of aparticular definition, but should be understood in the conventionalsense. When a trade name appears herein, it is intended to refer to itscorresponding commodity or active ingredient thereof.

The term “pharmaceutically acceptable” is used herein in terms of thosecompounds, materials, compositions, and/or dosage forms, which aresuitable for use in contact with human and animal tissues within thescope of reliable medical judgment, with no excessive toxicity,irritation, allergic reaction or other problems or complications,commensurate with a reasonable benefit/risk ratio.

The term “pharmaceutically acceptable salt” means a salt of compoundsdisclosed herein that is prepared by reacting the compound having aspecific substituent disclosed herein with a relatively non-toxic acidor base. When compounds disclosed herein contain a relatively acidicfunctional group, a base addition salt can be obtained by bringing thecompound into contact with a sufficient amount of base in a puresolution or a suitable inert solvent. The pharmaceutically acceptablebase addition salt includes a salt of sodium, potassium, calcium,ammonium, organic amine or magnesium or similar salts. When compoundsdisclosed herein contain a relatively basic functional group, an acidaddition salt can be obtained by bringing the compound into contact witha sufficient amount of acid in a pure solution or a suitable inertsolvent. Examples of the pharmaceutically acceptable acid addition saltinclude an inorganic acid salt, wherein the inorganic acid includes, forexample, hydrochloric acid, hydrobromic acid, nitric acid, carbonicacid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogenphosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorousacid, and the like; and an organic acid salt, wherein the organic acidincludes, for example, acetic acid, propionic acid, isobutyric acid,maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid,fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonicacid, p-toluenesulfonic acid, citric acid, tartaric acid, andmethanesulfonic acid, and the like; and an salt of amino acid (such asarginine and the like), and a salt of an organic acid such as glucuronicacid and the like. Certain specific compounds disclosed herein containboth basic and acidic functional groups and can be converted to any baseor acid addition salt.

The pharmaceutically acceptable salt disclosed herein can be preparedfrom the parent compound that contains an acidic or basic moiety byconventional chemical methods. Generally, such salt can be prepared byreacting the free acid or base form of the compound with astoichiometric amount of an appropriate base or acid in water or anorganic solvent or a mixture thereof.

Compounds disclosed herein may be present in a specific geometric orstereoisomeric form. The present disclosure contemplates all suchcompounds, including cis and trans isomers, (−)- and (+)-enantiomers,(R)- and (S)-enantiomers, diastereoisomer, (D)-isomer, (L)-isomer, and aracemic mixture and other mixtures, for example, a mixture enriched inenantiomer or diastereoisomer, all of which are encompassed within thescope disclosed herein. The substituent such as alkyl may have anadditional asymmetric carbon atom. All these isomers and mixturesthereof are encompassed within the scope disclosed herein.

Compounds disclosed herein may contain an unnatural proportion of atomicisotopes at one or more of the atoms that make up the compounds. Forexample, a compound may be labeled with a radioisotope such as tritium(³H), iodine-125 (¹²⁵I) or C-14 (¹⁴C). For another example, hydrogen canbe replaced by heavy hydrogen to form a deuterated drug. The bondbetween deuterium and carbon is stronger than that between ordinaryhydrogen and carbon. Compared with undeuterated drugs, deuterated drugshave advantages of reduced toxic side effects, increased drug stability,enhanced efficacy, and prolonged biological half-life of drugs. Allchanges in the isotopic composition of compounds disclosed herein,regardless of radioactivity, are included within the scope of thepresent disclosure.

The term “optional” or “optionally” means that the subsequent event orcondition may occur but not requisite, that the term includes theinstance in which the event or condition occurs and the instance inwhich the event or condition does not occur.

The term “substituted” means that one or more than one hydrogen atoms ona specific atom are substituted by a substituent, including deuteriumand hydrogen variants, as long as the valence of the specific atom isnormal and the substituted compound is stable. When the substituent isoxo (i.e., ═O), it means two hydrogen atoms are substituted. Positionson an aromatic ring cannot be substituted by oxo. The term “optionallysubstituted” means an atom can be substituted by a substituent or not,unless otherwise specified, the species and number of the substituentmay be arbitrary so long as being chemically achievable.

When any variable (such as R) occurs in the constitution or structure ofthe compound more than once, the definition of the variable at eachoccurrence is independent. Thus, for example, if a group is substitutedby 0-2 R, the group can be optionally substituted by up to two R,wherein the definition of R at each occurrence is independent. Moreover,a combination of the substituent and/or the variant thereof is allowedonly when the combination results in a stable compound.

When the number of a linking group is 0, such as —(CRR)₀—, it means thatthe linking group is a single bond.

When one of variables is a single bond, it means that the two groupslinked by the single bond are connected directly. For example, when L inA-L-Z represents a single bond, the structure of A-L-Z is actually A-Z.

When an enumerated linking group does not indicate its linkingdirection, its linking direction is arbitrary. For example, when thelinking group L in

is -M-W—, the -M-W— can be linked to the ring A and the ring B in thesame direction as the reading order from left to right to constitute

or can be linked to the ring A and the ring B in the reverse directionas the reading order from left to right to constitute

A combination of the linking groups, substituents and/or variantsthereof is allowed only when such combination can result in a stablecompound.

Unless otherwise specified, when a group has one or more connectablesites, any one or more sites of the group can be connected to othergroups through chemical bonds. Where the connection position of thechemical bond is variable, and there is H atom(s) at a connectablesite(s), when the connectable site(s) having H atom(s) is connected tothe chemical bond, the number of H atom(s) at this site willcorrespondingly decrease as the number of the connected chemical bondincreases, and the group will become a group of corresponding valence.The chemical bond between the site and other groups can be representedby a straight solid bond (

), a straight dashed bond (

), or a wavy line (

). For example, the straight solid bond in —OCH₃ indicates that thegroup is connected to other groups through the oxygen atom in the group;the straight dashed bond in

indicates that the group is connected to other groups through two endsof the nitrogen atom in the group; the wavy line in

indicates that the group is connected to other groups through the 1- and2-carbon atoms in the phenyl group;

indicates that any connectable site on the piperidinyl group can beconnected to other groups through one chemical bond, including at leastfour connection ways,

even if a H atom is drawn on —N—,

still includes the connection way of

it's just that when one chemical bond is connected, the H at this sitewill be reduced by one, and the group will become the correspondingmonovalent piperidinyl group.

Unless otherwise specified, a wedged solid bond (

) and a wedged dashed bond (

) indicate the absolute configuration of a stereocenter; a straightsolid bond (

) and a straight dashed bond (

) indicate the relative configuration of a stereocenter; a wavy line (

) indicates a wedged solid bond (

) or a wedged dashed bond (

); or a wavy line (

) indicates a straight solid bond (

) and a straight dashed bond (

). For example,

Unless otherwise specified, the term “enriched in one isomer”, “isomerenriched”, “enriched in one enantiomer” or “enantiomeric enriched” meansthat the content of one isomer or enantiomer is less than 100%, and thecontent of the isomer or enantiomer is 60% or more, or 70% or more, or80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% ormore, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% ormore, or 99.7% or more, or 99.8% or more, or 99.9% or more.

Unless otherwise specified, the term “isomer excess” or “enantiomericexcess” means the difference between the relative percentages of twoisomers or two enantiomers. For example, if one isomer or enantiomer ispresent in an amount of 90% and the other isomer or enantiomer ispresent in an amount of 10%, the isomer or enantiomeric excess (eevalue) is 80%.

Optically active (R)- and (S)-isomer, or D and L isomer can be preparedusing chiral synthesis or chiral reagents or other conventionaltechniques. If one kind of enantiomer of certain compound disclosedherein is to be obtained, the pure desired enantiomer can be obtained byasymmetric synthesis or derivative action of chiral auxiliary followedby separating the resulting diastereomeric mixture and cleaving theauxiliary group. Alternatively, when the molecule contains a basicfunctional group (such as amino) or an acidic functional group (such ascarboxyl), the compound reacts with an appropriate optically active acidor base to form a salt of the diastereomeric isomer which is thensubjected to diastereomeric resolution through the conventional methodin the art to afford the pure enantiomer. In addition, the enantiomerand the diastereoisomer are generally isolated through chromatographywhich uses a chiral stationary phase and optionally combines with achemical derivative method (for example, carbamate generated fromamine).

Unless otherwise specified, the term “C₁₋₆ alkyl” is used to represent alinear or branched saturated hydrocarbon group composed of 1 to 6 carbonatoms. The C₁₋₆ alkyl includes C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆, C₂₋₄, C₆,and C₅ alkyl, etc. It may be monovalent (such as methyl), divalent (suchas methylene) or multivalent (such as methenyl). Examples of the C₁₋₆alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl(including n-propyl and isopropyl), butyl (including n-butyl, isobutyl,s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl andneopentyl), hexyl, and the like.

Unless otherwise specified, the term “C₁₋₃ alkyl” is used to represent alinear or branched saturated hydrocarbon group composed of 1 to 3 carbonatoms. The C₁₋₃ alkyl includes C₁₋₂ alkyl, C₂₋₃ alkyl, etc. It may bemonovalent (such as methyl), divalent (such as methylene) or multivalent(such as methenyl). Examples of the C₁₋₃ alkyl include, but are notlimited to, methyl (Me), ethyl (Et), propyl (including n-propyl andisopropyl), and the like.

Unless otherwise specified, the term “C₁₋₃ alkoxy” means alkyl groupscontaining 1 to 3 carbon atoms and attached to the remainder of amolecule by an oxygen atom. The C₁₋₃ alkoxy group includes C₁₋₂, C₂₋₃,C₃, and C₂ alkoxy groups, and the like. Examples of C₁₋₃ alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy (includingn-propoxy and isopropoxy), and the like.

Unless otherwise specified, the term “C₁₋₃ alkylamino” means alkylgroups containing 1 to 3 carbon atoms and attached to the remainder of amolecule by an amino group. The C₁₋₃ alkylamino group includes C₁₋₂, C₃and C₂ alkylamino groups and the like. Examples of C₁₋₃ alkylaminogroups include, but are not limited to —NHCH₃, —N(CH₃)₂, —NHCH₂CH₃,—N(CH₃)CH₂CH₃, —NHCH₂CH₂CH₃, —NHCH₂(CH₃)₂, and the like.

Unless otherwise specified, “C₂₋₃ alkenyl” is used to represent a linearor branched hydrocarbon group composed of 2 to 3 carbon atoms containingat least one carbon-carbon double bond, wherein the carbon-carbon doublebond can be located at any position of the group. The C₂₋₃ alkenylincludes C₃ and C₂ alkenyl. The C₂₋₃ alkenyl may be monovalent, divalentor multivalent. Examples of the C₂₋₃ alkenyl include, but are notlimited to, vinyl, propenyl, and the like.

Unless otherwise specified, “C₂₋₃ alkynyl” is used to represent a linearor branched hydrocarbon group composed of 2 to 3 carbon atoms containingat least one carbon-carbon triple bond, wherein the carbon-carbon triplebond can be located at any position of the group. The C₂₋₃ alkynylincludes C₃ and C₂ alkynyl. Examples of the C₂₋₃ alkynyl include, butare not limited to, ethynyl, propynyl, and the like.

Unless otherwise specified, the terms “C₆₋₁₀ aromatic ring” and “C₆₋₁₀aryl” may be used interchangeably in this disclosure. The term “C₆₋₁₀aromatic ring” or “C₆₋₁₀ aryl” means a cyclic hydrocarbon group having aconjugated pi electron system and composed of 6 to 10 carbon atoms. Itmay be a monocyclic, fused bicyclic or fused tricyclic ring system,wherein each ring is aromatic. It may be monovalent, divalent ormultivalent. The C₆₋₁₀ aryl includes C₆₋₉, C₉, C₁₀ and C₆ aryl, etc.Examples of C₆₋₁₀ aryl include, but are not limited to, phenyl, naphthyl(including 1-naphthyl and 2-naphthyl, etc.).

Unless otherwise specified, the terms “5- to 10-membered heteroaromaticring” and “5- to 10-membered heteroaryl” may be used interchangeably.The term “5- to 10-membered heteroaryl” means a cyclic group having aconjugated pi electron system and composed of 5 to 10 ring atoms, inwhich 1, 2, 3 or 4 ring atoms are heteroatoms independently selectedfrom O, S and N, and the remainder is carbon atoms. It may be amonocyclic, fused bicyclic or fused tricyclic ring system, wherein eachring is aromatic, and wherein the nitrogen atom is optionallyquaternized and the nitrogen and sulfur heteroatoms are optionallyoxidized (i.e., NO and S(O)_(p), p is 1 or 2). A 5- to 10-memberedheteroaryl can be attached to the remainder of the molecule through aheteroatom or a carbon atom. The 5- to 10-membered heteroaryl groupincludes 5- to 8-membered, 5- to 7-membered, 5- to 6-membered,5-membered and 6-membered heteroaryl groups. Examples of the 5-10membered heteroaryl include, but are not limited to, pyrrolyl (includingN-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including2-pyrazolyl and 3-pyrazolyl, and the like), imidazolyl (includingN-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, and thelike), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, andthe like), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl,1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, and the like), tetrazolyl,isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, and the like),thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, and thelike), furyl (including 2-furyl and 3-furyl, and the like), thienyl(including 2-thienyl and 3-thienyl, and the like), pyridyl (including2-pyridyl, 3-pyridyl and 4-pyridyl, and the like), pyrazinyl orpyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, and the like),benzothiazolyl (including 5-benzothiazolyl, and the like), purinyl,benzimidazolyl (including 2-benzimidazolyl, and the like), benzoxazolyl,indolyl (including 5-indolyl, and the like), isoquinolyl (including1-isoquinolyl, 5-isoquinolyl, and the like), quinoxalinyl (including2-quinoxalinyl, 5-quinoxalinyl, and the like) or quinolyl (including3-quinolyl, 6-quinolyl, and the like).

Unless otherwise specified, the term “4- to 8-membered heterocycloalkyl”alone or in combination with other terms respectively represents asaturated cyclic group composed of 4 to 8 ring atoms, in which 1, 2, 3or 4 ring atoms are heteroatoms independently selected from O, S and N,and the remainder is carbon atoms, wherein the nitrogen atom isoptionally quaternized, and the nitrogen and sulfur heteroatoms areoptionally oxidized (i.e., NO and S(O)_(p), p is 1 or 2). The ringcomprises monocyclic and bicyclic ring systems, wherein the bicyclicring systems comprise spiro, fused, and bridged cyclic rings. Inaddition, with respect to the “4- to 8-membered heterocycloalkyl”, theheteroatom may be present on the position of attachment of theheterocycloalkyl group to the remainder of a molecule. The 4- to8-membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4membered, 5 membered, and 6 membered heterocycloalkyl, etc. Examples ofthe 4- to 8-membered heterocycloalkyl include, but are not limited to,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl andtetrahydrothien-3-yl and the like), tetrahydrofuranyl (includingtetrahydrofuran-2-yl and the like), tetrahydropyranyl, piperidinyl(including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl and the like),piperazinyl (including 1-piperazinyl and 2-piperazinyl and the like),morpholinyl (including 3-morpholinyl and 4-morpholinyl and the like),dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl,1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl ordioxepanyl, and the like.

Unless otherwise specified, C_(n−n+m) or C_(n)-C_(n+m) includes anyspecific case of n to n+m carbons, for example, C₁₋₁₂ includes C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂, also includes any rangefrom n to n+m, for example, C₁₋₁₂ includes C₁₋₃, C₁₋₆, C₁₋₉, C₃₋₆, C₃₋₉,C₃₋₁₂, C₆₋₉, C₆₋₁₂ and C₉₋₁₂, etc.; similarly, n membered to n+mmembered indicates that the number of atoms on a ring is n to n+m, forexample, 3-12 membered ring includes 3 membered ring, 4 membered ring, 5membered ring, 6 membered ring, 7 membered ring, 8 membered ring, 9membered ring, 10 membered ring, 11 membered ring, and 12 membered ring,also includes any range from n to n+m, for example, 3-12 membered ringincludes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring, 5-7membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 memberedring, and the like.

The term “leaving group” refers to a functional group or atom which canbe replaced by another functional group or atom through a substitutionreaction (such as nucleophilic substitution reaction). For example,representative leaving groups include triflate; chlorine, bromine andiodine; sulfonate group, such as mesylate, tosylate,p-bromobenzenesulfonate, p-toluenesulfonate and the like; acyloxy, suchas acetoxy, trifluoroacetoxy and the like.

The term “protecting group” includes, but is not limited to “aminoprotecting group”, “hydroxy protecting group” or “thio protectinggroup”. The term “amino protecting group” refers to a protecting groupsuitable for blocking the side reaction on the nitrogen of an amino.Representative amino protecting groups include, but are not limited to:formyl; acyl, such as alkanoyl (e.g. acetyl, trichloroacetyl ortrifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc);arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn),trityl (Tr), 1,1-bis-(4′-methoxyphenyl)methyl; silyl such astrimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like. Theterm “hydroxy protecting group” refers to a protecting group suitablefor blocking the side reaction on hydroxy. Representative hydroxyprotecting groups include, but are not limited to: alkyl such as methyl,ethyl and tert-butyl; acyl such as alkanoyl (e.g. acetyl); arylmethylsuch as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), anddiphenylmethyl (benzhydryl, DPM); silyl such as trimethylsilyl (TMS) andtert-butyl dimethyl silyl (TBS) and the like.

Compounds disclosed herein can be prepared by a variety of syntheticmethods well known to those skilled in the art, including the followingenumerated embodiment, the embodiment formed by the following enumeratedembodiment in combination with other chemical synthesis methods, andequivalent replacement well known to those skilled in the art.Alternative embodiments include, but are not limited to the embodimentdisclosed herein.

The structures of compounds disclosed herein can be confirmed byconventional methods well known to those skilled in the art. If thepresent disclosure relates to an absolute configuration of a compound,the absolute configuration can be confirmed by conventional techniquesin the art, such as single crystal X-Ray diffraction (SXRD). In thesingle crystal X-Ray diffraction (SXRD), the diffraction intensity dataof the cultivated single crystal is collected using a Bruker D8 venturediffractometer with a light source of CuKα radiation in a scanning modeof φ/ω scan; after collecting the relevant data, the crystal structureis further analyzed by the direct method (Shelxs97) to confirm theabsolute configuration.

Solvents used in the present disclosure are commercially available.

Compounds are named according to general naming principles in the art orby ChemDraw® software, and commercially available compounds are namedwith their vendor directory names.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows changes in tumor volume over time at different doses.

FIG. 2 shows changes in animal body weight over time at different doses.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure is described in detail below by means ofexamples. However, it is not intended that these examples have anydisadvantageous limitations to the present disclosure. The presentdisclosure has been described in detail herein, and embodiments are alsodisclosed herein. It will be apparent to those skilled in the art thatvarious changes and modifications may be made to the embodimentsdisclosed herein without departing from the spirit and scope disclosedherein.

Example 1

Step 1: Synthesis of Compound 1-2

Compound 1-1 (10 g, 64.03 mmol, 8.70 mL, 1 eq) and tert-butylsulfinamide (7.76 g, 64.03 mmol, 1 eq) were dissolved in tetrahydrofuran(100 mL), and tetraethyl titanate (29.21 g, 128.06 mmol, 26.56 mL, 2 eq)was then added. The mixture was stirred at 25° C. for 10 hr. After thereaction was completed, 10 g of ice was added under an ice-water bathand a large amount of solid was precipitated. Then tetrahydrofuran (100mL) was added, and the mixture was filtered. The filtrate was collectedand concentrated to give compound 1-2, which was directly used in thenext reaction step. ¹H NMR (400 MHz, CDCl₃) δ=9.17 (s, 1H), 9.05 (d,J=8.5 Hz, 1H), 8.05 (dd, J=7.9, 10.8 Hz, 2H), 7.94 (d, J=8.1 Hz, 1H),7.72-7.63 (m, 1H), 7.59 (t, J=7.6 Hz, 2H), 1.34 (s, 9H); LCMS m/z=260.1[M+1]⁺.

Step 2: Synthesis of Compound 1-3

Methyl acetate (4.28 g, 57.83 mmol, 4.60 mL, 1.5 eq) was dissolved intetrahydrofuran (100 mL) and the mixture was cooled down to −78° C.under nitrogen. Lithium hexamethyldisilazide (1 M, 59.76 mL, 1.55 eq)was added slowly dropwise to the reaction solution. After stirring at−78° C. for 1 hr, compound 1-2 (10 g, 38.56 mmol, 1 eq) was added slowlydropwise to the reaction solution and the mixture was stirred at thistemperature for another 1 hr. After the reaction was completed, thereaction solution was poured into saturated aqueous ammonium chloridesolution (80 mL) and extracted with ethyl acetate (50 mL×3). The organicphases were combined, washed with saturated brine, dried over anhydroussodium sulfate, and filtered. The filtrate was collected andconcentrated. The crude product was purified by column chromatography(petroleum ether/ethyl acetate=50/1-1/1) to give compound 1-3. ¹H NMR(400 MHz, CDCl₃) δ=8.17 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.82(d, J=8.0 Hz, 1H), 7.57 (t, J=6.8 Hz, 2H), 7.54-7.52 (m, 1H), 7.52-7.44(m, 2H), 4.78 (d, J=2.4 Hz, 1H), 3.69 (s, 3H), 3.09 (d, J=6.4 Hz, 2H),1.25-1.22 (s, 9H); LCMS m/z=334.1 [M+1]⁺.

Step 3: Synthesis of Compound 1-4

Compound methyl acetate (5.55 g, 74.98 mmol, 5.96 mL, 5 eq) wasdissolved in tetrahydrofuran (50 mL) and the mixture was cooled down to−78° C. under nitrogen. Sodium hexamethyldisilazide (1 M, 74.98 mL, 5eq) was added to the reaction solution. After stirring at −78° C. for 1hr, compound 1-3 (5 g, 15.00 mmol, 1 eq) was added slowly dropwise tothe reaction solution and the mixture was stirred at this temperaturefor another 1 hr. After the reaction was completed, the reactionsolution was poured into saturated aqueous ammonium chloride solution(50 mL) and extracted with ethyl acetate (50 mL×3). The organic phaseswere combined, washed with saturated brine (50 mL), dried over anhydroussodium sulfate, and filtered. The filtrate was collected andconcentrated to give compound 1-4, which was directly used in the nextreaction step. LCMS m/z=376.1 [M+1]⁺.

Step 4: Synthesis of Compound 1-5

Compound 1-4 (5 g, 13.32 mmol, 11.92 mL, 1 eq) was dissolved in toluene(50 mL) and N,N-dimethylformamide dimethyl acetal (15.87 g, 133.16 mmol,17.69 mL, 10 eq) was added and the mixture was stirred to react at 19°C. for 10 hr. After the reaction was completed, the reaction solutionwas poured into saturated aqueous ammonium chloride solution (80 mL) andextracted with ethyl acetate (50 mL×3). The organic phases werecombined, washed with saturated brine, dried over anhydrous sodiumsulfate, and filtered. The filtrate was collected and concentrated. Thecrude product was purified by column chromatography(dichloromethane/methanol=100/1-10/1) to give compound 1-5. LCMSm/z=431.1 [M+1]⁺.

Step 5: Synthesis of compound 1-6:

Compound 1-5 (2.4 g, 5.57 mmol, 1 eq) was dissolved inhydrochloride/dioxane (4 M, 60.00 mL) and the mixture was stirred at 18°C. for 10 hr. After the reaction was completed, the reaction solutionwas directly concentrated to give the hydrochloride salt of compound1-6, which was directly used in the next reaction step. LCMS m/z=282.1[M+1]⁺.

Step 6: Synthesis of Compound 1-7

Compound 1-6 hydrochloride (2 g, 6.29 mmol, 1 eq) was dissolved inN,N-dimethylformamide (20 mL), and then potassium carbonate (6.15 g,18.88 mmol, 3 eq) and iodomethane (1.79 g, 12.59 mmol, 783.65 μL, 2 eq)were added sequentially and stirred at 18° C. for 10 h. After thereaction was completed, the reaction solution was poured into water (30mL) and extracted with ethyl acetate (30 mL×2). The combined organicphase was washed with saturated brine (50 mL), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated to give acrude product. The crude product was purified by column chromatography(dichloromethane/methanol=50/1-10/1) to give compound 1-7. ¹H NMR (400MHz, CDCl₃) δ=8.47 (s, 1H), 7.96-7.88 (m, 2H), 7.85 (d, J=8.4 Hz, 1H),7.62-7.51 (m, 2H), 7.48-7.41 (m, 1H), 7.35 (d, J=7.0 Hz, 1H), 5.52-5.39(m, 1H), 3.83 (s, 3H), 3.19 (s, 3H), 3.23-3.14 (m, 1H), 2.98-2.87 (m,1H).

Step 7: Synthesis of Compound 1-8

Compound 1-7 (20 mg, 67.72 μmol, 1 eq) was dissolved in ethanol (0.2 mL)and 1,4-dioxane (1 mL). Nickel chloride hexahydrate (19.32 mg, 81.26μmol, 1.2 eq) was then added. After cooling down to 5-10° C., sodiumborohydride (1.28 mg, 33.86 μmol, 0.5 eq) was added and the mixture wasreacted at 10° C. for 0.5 h. After the reaction was completed, themixture was poured into saturated aqueous ammonium chloride solution (5mL) and extracted with ethyl acetate (10 mL×2). The combined organicphase was washed with saturated brine (5 mL), dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated to give acrude product. The crude product was purified by thin-layerchromatography preparative plate (developer: petroleum ether/ethylacetate=3/1) to give compound 1-8. ¹H NMR (400 MHz, CDCl₃) δ=11.99-11.85(m, 1H), 8.67-8.49 (m, 1H), 7.92-7.85 (m, 1H), 7.85-7.77 (m, 1H),7.57-7.41 (m, 4H), 3.82 (s, 3H), 3.56-3.51 (m, 1H), 3.16-2.95 (m, 2H),2.68-2.47 (m, 1H), 2.15 (s, 3H).

Step 8: Synthesis of Compound 1-9

Compound 1-8 (240 mg, 807.14 μmol, 1 eq) and urea (242.36 mg, 4.04 mmol,216.40 μL, 5 eq) were dissolved in ethanol (5 mL) and sodium methoxide(130.80 mg, 2.42 mmol, 3 eq) was added. After reacting at 85° C. for 10hr, the reaction solution was slowly poured into water and then ethylacetate (5 mL) was added. Solids were precipitated. The mixture wasfiltered, and the solid was collected to give compound 1-9. LCMSm/z=308.1 [M+1]⁺.

Step 9: Synthesis of Compound 1-10

Compound 1-9 (400 mg, 1.30 mmol, 1 eq) was dissolved in phosphorusoxychloride (132.00 g, 860.89 mmol, 80 mL). The mixture was heated to105° C. to react for 10 h and then concentrated under reduced pressureto remove the excess phosphorus oxychloride. The residue was dissolvedin ethyl acetate (50 mL) and the solution was then added to saturatedaqueous sodium bicarbonate solution (20 mL). The aqueous phase wasextracted with ethyl acetate (50 mL×3). The combined organic phase waswashed with saturated brine (50 mL), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated to give a crudeproduct. The crude product was purified by thin layer chromatographycolumn (eluent: petroleum ether/ethyl acetate=20/1-0/1) to give compound1-10. LCMS m/z=344.0 [M+1]⁺.

Step 10: Synthesis of Compound 1-11

Compound 1-10 (250 mg, 726.24 μmol, 1 eq) and intermediate 1-10Ahydrochloride (279.24 mg, 944.12 μmol, 1.3 eq) were dissolved inisopropanol (2 mL), and N,N-diisopropylethylamine (375.44 mg, 2.90 mmol,505.98 μL, 4 eq) was added. After reacting at 110° C. for 12 hr, thereaction solution was concentrated directly. The residue was purified bycolumn chromatography (eluent: petroleum ether/ethyl acetate=10/1-1/1)to give compound 1-11. ¹H NMR (400 MHz, CDCl₃) δ=8.60-8.48 (m, 1H),7.93-7.87 (m, 1H), 7.86-7.80 (m, 1H), 7.58-7.34 (m, 9H), 5.21 (m, 2H),4.77-4.61 (m, 1H), 4.06 (m, 2H), 3.97-3.75 (m, 2H), 3.62-3.40 (m, 3H),3.30-3.00 (m, 4H), 2.78-2.64 (m, 1H), 2.26 (s, 1.5H), 2.21 (s, 1.5H);LCMS m/z=567.3 [M+1]⁺.

Step 11: Synthesis of Compound 1-12

Compound 1-11 (100 mg, 176.34 μmol, 1 eq) and 1-11A (60.93 mg, 529.03μmol, 62.81 μL, 3 eq) were dissolved in 1,4-dioxane (1.5 mL), and cesiumcarbonate (172.37 mg, 529.03 μmol, 3 eq),2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (16.46 mg,35.27 μmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (32.30 mg,35.27 μmol, 0.2 eq) were added. The mixture was reacted at 90° C. undernitrogen for 24 hr. After the reaction was completed, the reactionmixture was concentrated directly. The residue was purified by columnchromatography (eluent: dichloromethane/methanol=100/1-10/1) to givecompound 1-12. LCMS m/z=646.4 [M+1]⁺.

Step 12: Synthesis of Compound 1-13

Compound 1-12 (50 mg, 77.42 μmol, 1 eq) was dissolved in tetrahydrofuran(50 mL) and Pd/C (77.4 mg, 10% purity) was added. The reaction systemwas replaced three times with H₂. The mixture was stirred to react at 15psi, 20° C. for 10 h. After the reaction was completed, the mixture wasfiltered to give a tetrahydrofuran solution of compound 1-13 (70 mL),which was used directly in the next step. LCMS m/z=512.3 [M+1]⁺.

Step 13: Synthesis of Compound 1

To the tetrahydrofuran solution of compound 1-13 (70 mL) obtained in theprevious step was added N,N-diisopropylethylamine (17.18 mg, 132.90μmol, 23.15 μL, 2 eq). The mixture was then cooled down to −20 to −30°C., and acryloyl chloride (6.01 mg, 66.45 μmol, 5.42 μL, 1 eq) wasadded. After 30 min of reaction at this temperature, the reactionsolution was poured into water (10 mL), and then extracted with ethylacetate (10 mL). The organic phase was dried with anhydrous sodiumsulfate, and filtered. The filtrate was concentrated to give a crudeproduct. The crude product was purified by a high-performance liquidchromatography column (column: Phenomenex Luna 80*30 mm*3 μm; mobilephase: [10 mM NH₄HCO₃ aqueous solution-acetonitrile]; acetonitrile %:30%-60%, 7 min) to give compound 1, which was consisted of twodiastereomers as identified by SFC (Chiralcel OD-3 column, P1 Rt=1.93min, P2 Rt=2.08 min, P1:P2=50.6:49.4). ¹H NMR (400 MHz, CDCl₃)δ=8.66-8.53 (m, 1H), 7.93-7.87 (m, 1H), 7.82 (d, J=8.0 Hz, 1H),7.56-7.41 (m, 4H), 6.70-6.50 (m, 1H), 6.47-6.34 (m, 1H), 5.84 (d, J=7.2Hz, 1H), 4.38 (m, 1H), 4.27-4.09 (m, 2H), 4.05-3.78 (m, 4H), 3.60-3.35(m, 3H), 3.23-3.01 (m, 4H), 2.84-2.60 (m, 3H), 2.50-2.41 (m, 3H),2.30-2.21 (m, 4H), 2.10-1.98 (m, 1H), 1.90-1.66 (m, 4H). LCMS m/z=566.4[M+1]⁺.

Examples 2 and 3

Step 1: Synthesis of Compound 2-2

Compound 2-1 (2.2 g, 9.11 mmol, 1 eq) was dissolved in anhydroustetrahydrofuran (15 mL) and the mixture was cooled down to −78° C. undernitrogen. Then n-BuLi (2.5 M, 3.64 mL, 1 eq) was added dropwise and themixture was stirred to react at −78° C. for 1 hr. N,N-dimethylformamide(3.33 g, 45.55 mmol, 3.50 mL, 5 eq) was added and the mixture wasstirred at −78° C. for another 0.5 hr. The reaction was quenched byadding saturated ammonium chloride solution (10 mL) and then water (10mL) was added. The organic phase was separated out and the aqueous phasewas extracted with ethyl acetate (50 mL). The combined organic phase wasdried with anhydrous sodium sulfate, and filtered to remove thedesiccant. The solvent was removed under reduced pressure to give acrude product. The crude product was purified by column (ethylacetate/petroleum ether=0-15%) to give compound 2-2. ¹H NMR (400 MHz,CDCl₃) δ=11.32 (s, 1H), 8.04 (dd, J=1.2, 8.0 Hz, 1H), 7.92 (dd, J=1.2,7.2 Hz, 1H), 7.87 (dd, J=1.2, 8.4 Hz, 1H), 7.71 (dd, J=1.2, 7.2 Hz, 1H),7.59 (t, J=7.6 Hz, 1H), 7.51-7.44 (m, 1H).

Step 2: Synthesis of Compound 2-3

Sodium hydride (248.01 mg, 6.20 mmol, 60% purity, 1.2 eq) was suspendedin anhydrous tetrahydrofuran (5 mL) and the mixture was cooled down to0° C. under nitrogen, to which methyl acetoacetate (600 mg, 5.17 mmol,555.56 μL, 1 eq) was then added dropwise. After stirring for 10 min,n-butyllithium (2.5 M, 2.27 mL, 1.1 eq) was added dropwise and themixture was stirred to react at 0° C. for another 20 min. The reactionsystem was then cooled down to −78° C. in a dry ice acetone bath and asolution of compound 2-2 (1.08 g, 5.68 mmol, 1.1 eq) in tetrahydrofuran(6 mL) was added dropwise. The reaction mixture was stirred for 30 min,then allowed to warm slowly to room temperature and stirred for 30 min.The reaction was quenched by adding water (30 mL) and the aqueous phasewas extracted with ethyl acetate (50 mL×2). The combined organic phasewas dried with sodium sulfate, and filtered to remove the desiccant. Thesolvent was removed from the filtrate under reduced pressure to give acrude product. The crude product was purified by column (ethylacetate/petroleum ether=0-20%) to give compound 2-3. ¹H NMR (400 MHz,CDCl₃) δ=8.07 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.63-7.49 (m,2H), 7.35 (t, J=8.0 Hz, 1H), 6.92 (br d, J=9.6 Hz, 1H), 3.75 (s, 3H),3.55 (s, 2H), 3.37 (dd, J=1.6, 18.1 Hz, 1H), 3.24 (d, J=1.2 Hz, 1H),2.86-2.77 (m, 1H).

Step 3: Synthesis of Compound 2-4

Compound 2-3 (520 mg, 1.70 mmol, 1 eq) was dissolved in dichloromethane(5 mL) and then N,N-dimethylformamide dimethylacetal (202.01 mg, 1.70mmol, 225.20 μL, 1 eq) was added. The resulting reaction solution wasstirred to react at 25° C. for 1 hr, and then Boron trifluoride etheratecomplex (240.60 mg, 1.70 mmol, 209.22 μL, 1 eq) was added and thereaction solution was stirred to react at 25° C. for 18 hr. The reactionsolution was concentrated under vacuum and the residue was adjusted topH of 3-4 with 2M hydrochloric acid. The mixture was then extracted withethyl acetate (30 mL×3). The combined organic phase was concentratedunder vacuum to give a crude product. The crude product was purified bycolumn (ethyl acetate/petroleum ether=0-35%) to give compound 2-4. ¹HNMR (400 MHz, CDCl₃) δ=8.56 (d, J=0.8 Hz, 1H), 7.91 (t, J=8.0 Hz, 2H),7.85 (dd, J=1.2, 8.4 Hz, 1H), 7.65 (dd, J=1.6, 7.6 Hz, 1H), 7.59 (t,J=8.0 Hz, 1H), 7.44-7.35 (m, 2H), 3.87 (s, 3H), 3.27-3.17 (m, 1H),2.92-2.82 (m, 1H). LCMS m/z=317.0 [M+H]⁺.

Step 4: Synthesis of Compound 2-5

Compound 2-4 (780 mg, 2.46 mmol, 1 eq) was dissolved in tetrahydrofuran(3 mL) and the mixture was cooled down to −78° C. under nitrogen. Thenlithium tri-sec-butylborohydride (1 M, 2.46 mL, 1 eq) was added dropwiseand the mixture was stirred to react at −78° C. for 1 hr. The reactionwas quenched with saturated ammonium chloride (5 mL) and then extractedwith ethyl acetate (50 mL×3). The organic phases were combined andconcentrated under vacuum to give a crude product. The crude product waspurified by column (ethyl acetate/petroleum ether=0-15%) to givecompound 2-5. ¹H NMR (400 MHz, CDCl₃) δ=11.81 (s, 1H), 7.99 (d, J=7.2Hz, 1H), 7.85-7.80 (m, 2H), 7.63-7.53 (m, 2H), 7.36 (t, J=7.6 Hz, 1H),6.30 (dd, J=2.8, 10.4 Hz, 1H), 4.68-4.62 (m, 1H), 4.56-4.47 (m, 1H),3.82 (s, 3H), 3.07-2.98 (m, 1H), 2.57-2.46 (m, 1H).

Step 5: Synthesis of Compound 2-6

Compound 2-5 (497 mg, 1.56 mmol, 1 eq) was dissolved in methanol (2 mL),then 2-methylthiourea sulfate (528.27 mg, 2.81 mmol, 1.8 eq) and sodiummethoxide (421.14 mg, 7.80 mmol, 5 eq) were added. The resultingreaction solution was stirred at 25° C. under nitrogen for 18 hr. Themethanol was removed under reduced pressure and water (1 mL) was addedto the residue. The mixture was adjusted to pH of 5-6 with 2 Mhydrochloric acid, and a large amount of white solid was precipitated.The solid was collected by filtration and dried under vacuum to givecompound 2-6. The crude product was used directly in the next reactionstep. LCMS m/z=359.1 [M+H]⁺.

Step 6: Synthesis of Compound 2-7

Compound 2-6 (440.00 mg, 1.23 mmol, 1 eq) and N,N-diisopropylethylamine(316.95 mg, 2.45 mmol, 427.15 μL, 2 eq) were added to anhydrousdichloromethane (5 mL) and the mixture was cooled down to 0° C. Triflicanhydride (449.74 mg, 1.59 mmol, 263.00 μL, 1.3 eq) was added. After theaddition was completed, the mixture was stirred to react at 0° C. for 60min. The reaction solution was concentrated under vacuum to give a crudeproduct, which was purified by column (ethyl acetate/petroleumether=0-6%) to give compound 2-7. ¹H NMR (400 MHz, CDCl₃) δ=7.99 (d,J=7.2 Hz, 1H), 7.90-7.82 (m, 2H), 7.66-7.54 (m, 2H), 7.44-7.33 (m, 1H),6.46 (dd, J=2.4, 10.4 Hz, 1H), 5.12-5.04 (m, 1H), 4.97-4.89 (m, 1H),3.63 (dd, J=2.0, 18.0 Hz, 1H), 3.05-2.90 (m, 1H), 2.57 (s, 3H). LCMSm/z=491.0 [M+H]⁺.

Step 7: Synthesis of Compound 2-8

Compound 2-7 (121 mg, 246.48 μmol, 1 eq) and N,N-diisopropylethylamine(95.57 mg, 739.45 μmol, 128.80 μL, 3 eq) were added toN,N-dimethylformamide (1.5 mL), followed by compound 1-10A hydrochloride(70.31 mg, 237.71 μmol, 1.1 eq). The gas in the reaction solution wasreplaced with nitrogen and the reaction solution was stirred in an oilbath at 100° C. to react for 1 hr. The reaction solution wasconcentrated under vacuum to give a crude product, which was purified bycolumn (ethyl acetate/petroleum ether=0-30%) to give compound 2-8. LCMSm/z=600.2 [M+H]⁺.

Step 8: Synthesis of Compound 2-9

Compound 2-8 (125 mg, 208.29 μmol, 1 eq) was dissolved indichloromethane (1 mL), then m-chloroperoxybenzoic acid (84.57 mg,416.58 μmol, 85% purity, 2 eq) was added, and the resulting reactionsolution was stirred to react at 20° C. for 8 hr. The reaction solutionwas filtered to remove insoluble matter and the filtrate wasconcentrated under vacuum to give a crude product, which was purified bycolumn (ethyl acetate/petroleum ether=0-60%) to give compound 2-9. LCMSm/z=632.3 [M+H]⁺.

Step 9: Synthesis of Compound 2-10

Compound 2-9 (101 mg, 159.78 μmol, 1 eq) and 1-11A (55.21 mg, 479.34μmol, 56.91 μL, 3 eq) were dissolved in toluene (0.8 mL). The resultingsolution was cooled down to −5° C., then t-BuONa (30.71 mg, 319.56 μmol,2 eq) was added, and the resulting reaction solution was stirred toreact at −5 to 0° C. for 1 hr. The reaction solution was diluted with 3mL of ethyl acetate and washed with water (1 mL) and saturated brine (1mL). The organic phase was concentrated under vacuum to give a crudeproduct, which was purified by column (methanol/dichloromethane=0-8%) togive compound 2-10. LCMS m/z=667.3 [M+H]⁺.

Step 10: Synthesis of a Mixture of Compounds 2-11 and 3-1

Compound 2-10 (101 mg, 151.38 μmol, 1 eq) was dissolved indichloromethane (1 mL), then palladium acetate (6.80 mg, 30.28 μmol, 0.2eq) and triethylsilane (88.01 mg, 756.90 μmol, 120.90 μL, 5 eq) wereadded, and the resulting reaction solution was stirred to react at roomtemperature for 1 hr. The reaction solution was concentrated undervacuum to give a mixture of compounds 2-11 and 3-1, which was useddirectly in the next reaction step without purification. Compound 2-11:LCMS m/z=555.3 [M+Na]⁺; Compound 3-1: LCMS m/z=521.3 [M+Na]⁺.

Step 11: Synthesis of Compounds 2 and 3

A mixture of compounds 2-11 and 3-1 was dissolved in dichloromethane (1mL) and then triethylamine (45.95 mg, 454.14 μmol, 63.21 μL, 3 eq) wasadded. The reaction solution was cooled down to 0° C., then acryloylchloride (20.55 mg, 227.07 μmol, 18.52 μL, 1.5 eq) was added and themixture was stirred to react for 30 min. The reaction solution wasconcentrated under vacuum to give a crude product, which was separatedby preparative high-performance liquid chromatography (separationconditions: column: Welch Xtimate C18 150*30 mm*5 μm; mobile phase:[water (0.225% formic acid)-acetonitrile]; acetonitrile %: 15%-55%, 8min) to give compounds 2 and 3. Compounds 2 and 3 were a pair ofdiastereoisomers, respectively. Compound 2: LCMS m/z=587.3 [M+H]⁺;Compound 3: LCMS m/z=553.3 [M+H]⁺.

Example 4

Synthesis of Intermediate 4-14A

Step 1: Synthesis of compound 4-21

Compound 4-20 (3 g, 8.35 mmol, 1 eq) was dissolved in tetrahydrofuran(30 mL), and wet palladium on carbon (1.2 g, 10% mass) was added. Theatmosphere was replaced three times with hydrogen (562.02 μg, 278.23μmol, 1 eq) and the mixture was reacted at room temperature of 25° C.,15 Psi for 2 hr. The reaction solution was filtered, and the motherliquor was collected and concentrated to give the compound 4-21. LCMSm/z=170.1[M-55+H]⁺.

Step 2: Synthesis of Compound 4-22

Compound 4-21 (0.2 g, 887.76 μmol, 1 eq) was dissolved intetrahydrofuran (5 mL), and triethylamine (269.50 mg, 2.66 mmol, 370.70μL, 3 eq) was added. The mixture was cooled down to 0° C. under nitrogenand trifluoroacetic anhydride (205.10 mg, 976.53 μmol, 135.83 μL, 1.1eq) was added. The mixture was reacted at 0° C. for 0.5 hr. The mixturewas poured into saturated aqueous ammonium chloride solution (10 mL),and ethyl acetate (5 mL*2) was added. The mixture was washed withsaturated brine (5 mL) and purified by column chromatography (petroleumether/ethyl acetate=10/1-1/1, TLC: petroleum ether/ethyl acetate=3/1) togive the compound 4-22. ¹H NMR (400 MHz, CDCl₃) δ=4.86 (s, 1H),4.51-4.06 (m, 2H), 3.88 (d, J=14.0 Hz, 1H), 3.52-3.33 (m, 1H), 3.24 (dd,J=4.0, 14.2 Hz, 1H), 3.12-2.92 (m, 1H), 2.91-2.73 (m, 1H), 2.67 (s, 1H),1.50 (s, 9H); LCMS: MS m/z=222.0 [M-100+H]⁺.

Step 3: Synthesis of Compound 4-14A

Compound 4-22 (150 mg, 466.86 μmol, 1 eq) was dissolved inhydrochloride/dioxane (5 M, 8 mL, 85.68 eq). The mixture was reacted at18° C. under nitrogen for 1 hr and then directly rotary-evaporated todryness to give the hydrochloride salt of compound 4-14A. LCMS: MSm/z=222.0 [M+H]⁺

Synthesis of Example 4

Step 1: Synthesis of Compound 4-2

After mixing water (210 mL) and hydrochloric acid (210 mL, 36-38% masscontent), compound 4-1 (36.00 g, 176.44 mmol, 1 eq) was added. Themixture was heated to 65° C., reacted for 1 hr, and then cooled down to0 to 5° C. A solution of sodium nitrite (14.61 g, 211.72 mmol, 1.2 eq)in water (70 mL) was added dropwise, and the mixture was stirred for 15min. Cuprous chloride (26.20 g, 264.65 mmol, 6.33 mL, 1.5 eq) wasdissolved in hydrochloric acid (350 mL, 36-38% mass content) and thesolution was cooled down to 0 to 5° C. The above solution was addeddropwise to the reaction solution, and the mixture was reacted foranother 6 hr. 750 mL of dichloromethane was added to the reactionsystem, and the mixture was stirred for 20 min. The layers wereseparated. The organic phase was washed once with 350 mL of saturatedbrine, dried with 30.00 g of anhydrous sodium sulfate, and filtered. Thefiltrate was rotary-evaporated under reduced pressure at 45° C. to givecompound 4-2. ¹H NMR (400 MHz, CDCl₃) δ=7.24-7.21 (m, 1H), 6.94 (dd,J=2.8, 8.8 Hz, 1H), 2.43 (s, 3H).

Step 2: Synthesis of Compound 4-3

Tetrahydrofuran (395 mL) and compound 4-2 (39.50 g, 176.76 mmol, 1 eq)were added to a pre-prepared clean reaction flask, and stirred. Themixture was cooled down to −70 to −65° C. Lithium diisopropylamide (2 M,106.05 mL, 1.2 eq) was added dropwise and the mixture was reacted foranother 1 hr. Then N,N-dimethylformamide (18.76 g, 256.70 mmol, 19.75mL, 1.45 eq) was added and the mixture was reacted for another 1 hr. 500mL of saturated ammonium chloride solution was added to the reactionsystem, and then the layers were separated. The organic phase was washedonce with 300 mL of saturated brine, then dried with 20 g of anhydroussodium sulfate, and filtered. The filtrate was rotary-evaporated underreduced pressure at 45° C. to give compound 4-3. ¹H NMR (400 MHz, CDCl₃)δ=10.28 (s, 1H), 7.08 (d, J=10.8 Hz, 1H), 2.51 (s, 3H); LCMSm/z=245.0[M+H]⁺, 247.0[M+3H]⁺.

Step 3: Synthesis of Compound 4-4

Dimethyl sulfoxide (300 mL) and compound 4-3 (20.00 g, 79.53 mmol, 1 eq)were added to a pre-prepared clean reaction flask and stirred. Thenhydrazine hydrate (48.75 g, 954.35 mmol, 47.33 mL, 98% mass content, 12eq) was added, and the mixture was heated to 130° C. and reacted for 3hr. The reaction solution was combined with a small-scale reactionsolution, and then the mixture was poured into 700 mL of water. Themixture was filtered, and the filter cake was washed with water (100mL×3 times). The obtained filter cake was dissolved in 300 mL of ethylacetate and the layers were separated. The organic phase was dried with50.00 g of anhydrous sodium sulfate and filtered. The filtrate wasrotary-evaporated under reduced pressure at 45° C. to give compound 4-4.¹H NMR (400 MHz, CDCl₃) δ=10.38 (brs, 1H), 8.03 (s, 1H), 7.33 (s, 1H),2.57 (s, 3H); LCMS m/z=245.1[M+H]⁺, 247.1[M+3H]⁺.

Step 4: Synthesis of Compound 4-5

Dichloromethane (200 mL) and compound 4-4 (20.00 g, 81.47 mmol, 1 eq)were added to a pre-prepared clean reaction flask and stirred. Thenpyridinium p-toluenesulfonate (2.05 g, 8.15 mmol, 0.1 eq) and2-methylhydroxy-3,4-dihydropyran (20.56 g, 244.40 mmol., 3 eq) wereadded sequentially. The mixture was reacted at 20° C. for 12 hr. After200 mL of water was added to the reaction system, the layers of thereaction solution was directly separated. The organic phase was driedwith 20.00 g of anhydrous sodium sulfate, and filtered. The filtrate wasrotary-evaporated under reduced pressure at 45° C. to give a crudecompound. The crude product was purified by column chromatography(petroleum ether/ethyl acetate=100/0-70/30, TLC: petroleum ether/ethylacetate=5/1) to give compound 4-5. ¹H NMR (400 MHz, CDCl₃) δ=7.95 (s,1H), 7.44 (s, 1H), 5.67 (dd, J=2.8, 8.8 Hz, 1H), 4.02-3.98 (m, 1H),3.79-3.71 (m, 1H), 2.57 (s, 3H), 2.54-2.46 (m, 1H), 2.18-2.05 (m, 2H),1.80-1.66 (m, 3H); LCMS m/z=329.0[M+H]⁺, 331.0[M+3H]⁺.

Step 5: Synthesis of Compound 4-6

Tetrahydrofuran (160 mL) and compound 4-5 (16 g, 48.54 mmol, 1 eq) wereadded to a pre-prepared clean reaction flask and stirred. After themixture was cooled down to −70 to −65° C., n-butyllithium (2.5 M, 21.36mL, 1.1 eq) was slowly added dropwise and the mixture was reacted foranother 1 hr. Then N,N-dimethylformamide (35.48 g, 485.41 mmol, 37.35mL, 10 eq) was added and the mixture was reacted for another 0.5 hr.After adding 250 mL of saturated ammonium chloride solution, the layerswere separated. The organic phase was washed once with 150 mL ofsaturated brine, dried with anhydrous sodium sulfate, and filtered. Thefiltrate was rotary-evaporated under reduced pressure at 45° C. to givean oily substance. The oily substance was mixed with 7 mL of ethylacetate. The mixture was slurried for 20 min, and then filtered. Thefilter cake was rotary-evaporated under reduced pressure at 45° C. togive compound 4-6. ¹H NMR (400 MHz, CDCl₃) δ=10.72 (s, 1H), 8.63 (s,1H), 7.74 (s, 1H), 5.70 (dd, J=2.8, 8.8 Hz, 1H), 3.98-3.94 (m, 1H),3.75-3.68 (m, 1H), 2.55 (s, 3H), 2.53-2.45 (m, 1H), 2.16-2.05 (m, 2H),1.83-1.61 (m, 3H); LCMS m/z=279.1[M+H]⁺.

Step 6: Synthesis of Compound 4-7

Tetrahydrofuran (54 mL) and compound 4-6 (5.4 g, 19.37 mmol, 1 eq) wereadded to a pre-prepared clean reaction flask and stirred. Thentert-butyl sulfinamide (2.58 g, 21.31 mmol, 232.15 μL, 1.1 eq) andtetraisopropyl titanate (8.84 g, 38.75 mmol, 8.04 mL, 2 eq) were added,and the mixture was reacted at 20° C. for 12 hr. After adding 50 mL ofsaturated ammonium chloride solution to the reaction system, the layerswere separated. The organic phase was dried with 3.00 g of anhydroussodium sulfate, and then filtered. The filtrate was rotary-evaporatedunder reduced pressure at 45° C. The crude product was purified bycolumn chromatography (petroleum ether/ethyl acetate=100/0 to 50/50,TLC: petroleum ether/ethyl acetate=10/1) to give compound 4-7. LCMSm/z=382.2[M+H]⁺.

Step 7: Synthesis of Compound 4-8

Tetrahydrofuran (35 mL) and sodium hydride (829.50 mg, 20.74 mmol, 60%mass content, 1.2 eq) were added to a pre-prepared clean reaction flask,and stirred. Then the mixture was cooled down to 0 to 5° C. and methylacetoacetate (2.41 g, 20.74 mmol, 2.23 mL, 1.2 eq) was added dropwise.The mixture was reacted for 20 min. Then n-butyllithium (2.5 M, 7.60 mL,1.1 eq) was added dropwise and the mixture was reacted for another 20min. After the mixture was cooled down to −70 to −65° C., a solution ofcompound 4-7 (6.60 g, 17.28 mmol, 1 eq) in tetrahydrofuran (35 mL) wasadded dropwise and the mixture was reacted for another 20 min. Themixture was slowly warmed to room temperature of 20° C. and reacted foranother 0.5 hr. The reaction solution was poured into 100 mL ofsaturated ammonium chloride solution. After combining with the 1 gbatch, the layers were separated. The organic phase was dried with 3.00g of anhydrous sodium sulfate and filtered. The filtrate wasrotary-evaporated under reduced pressure at 45° C. The crude product waspurified by column chromatography (petroleum ether/ethylacetate=100/0-20/80, TLC: PE/EtOAc=0:1) to give compound 4-8. ¹H NMR(400 MHz, CDCl₃) δ=8.20 (s, 1H), 7.44 (d, J=5.6 Hz, 1H), 5.72-5.64 (m,2H), 4.04-3.99 (m, 1H), 3.77-3.69 (m, 4H), 3.57-3.46 (m, 2H), 3.15-3.08(m, 1H), 2.59-2.52 (m, 4H), 2.16-2.05 (m, 2H), 1.83-1.65 (m, 4H),1.20-1.18 (m, 9H); LCMS m/z=498.2[M+H]⁺.

Step 8: Synthesis of Compound 4-9

Toluene (66 mL) and compound 4-8 (6.60 g, 13.25 mmol, 1 eq) were addedto a pre-prepared clean reaction flask and stirred. ThenN,N-dimethylformamide dimethyl acetal (4.74 g, 39.76 mmol, 5.28 mL, 3eq) was added, and the mixture was reacted at room temperature of 20° C.for 12 hr. 60 mL of water and 60 mL of ethyl acetate were added to thereaction system and the mixture was stirred for 5 min. The layers wereseparated. The organic phase was washed once with 60 mL of saturatedbrine, dried with 5.00 g of anhydrous sodium sulfate and filtered. Thefiltrate was rotary-evaporated under reduced pressure at 50° C. to givecompound 4-9, which was directly used in the next step.

Step 9: Synthesis of Compound 4-10

Compound 4-9 (50 mg, 90.40 μmol, 1 eq) was dissolved inhydrochloride/ethyl acetate (3 mL). The mixture was stirred at 18° C.for 20 min. The reaction solution was concentrated directly to give acrude product as a hydrochloride salt of compound 4-10. LCMS m/z=320.0[M+H]⁺

Step 10: Synthesis of Compound 4-11

Compound 4-10 (5.00 g, 14.04 mmol, 1 eq, HCl) was dissolved indichloromethane (50 mL), and triethylamine (5.97 g, 58.96 mmol, 8.21 mL,4.2 eq), tert-butyl dicarbonate (12.25 g, 56.15 mmol, 12.90 mL, 4 eq),and 4-dimethylaminopyridine (1.71 g, 14.04 mmol, 1 eq) were added. Thereaction mixture was stirred at 18° C. for 10 hr. The reaction mixturewas combined with the 0.5 g batch for treatment. The mixture wasquenched with saturated aqueous ammonium chloride solution (100 mL), andextracted with dichloromethane (30 mL*2 times). The combined organicphase was dried over anhydrous sodium sulfate and concentrated to give acrude product. The crude product was purified by column chromatography(petroleum ether/ethyl acetate=50/1-0/1, TLC: petroleum ether/ethylacetate=1/1) to give compound 4-11. ¹H NMR (400 MHz, CDCl₃) δ=9.02 (s,1H), 8.12 (s, 1H), 7.89 (s, 1H), 6.16 (dd, J=5.2, 8.8 Hz, 1H), 3.77 (s,3H), 3.10 (dd, J=8.4, 16.0 Hz, 1H), 2.82 (m, 1H), 2.48 (s, 3H), 1.63 (s,9H), 1.18 (s, 9H). LCMS m/z=520.1[M+H]⁺.

Step 11: Synthesis of Compound 4-12

Compound 4-11 (3.00 g, 5.77 mmol, 1 eq) was dissolved in tetrahydrofuran(30 mL), and the solution was cooled down to −78° C. Lithiumtri-sec-butylborohydride (1 M, 5.77 mL, 1 eq) was added dropwise to thereaction solution under nitrogen and the mixture was stirred for 0.5 hr.The reaction mixture was quenched with saturated aqueous ammoniumchloride solution (30 mL) and extracted with ethyl acetate (20 mL×2times). The organic phases were combined, dried with anhydrous sodiumsulfate, and concentrated to give a crude product of compound 4-12. LCMSm/z=522.2[M+H]⁺, 466.1[M-56+H]⁺.

Step 12: Synthesis of Compound 4-13

Compound 4-12 (2.30 g, 4.41 mmol, 1 eq) and 2-methyl-2-thioseudoureadisulfate (1.66 g, 8.81 mmol, 2 eq, H₂SO₄) were dissolved in methanol(430 mL), and sodium methoxide (476.05 mg, 8.81 mmol, 2 eq) was added.The mixture was stirred at 18° C. for 1.5 hr. Then sodium methoxide(357.04 mg, 6.61 mmol, 1.5 eq) was added to the reaction solution, andthe mixture was stirred at 18° C. for 10 hr. The mixture wasrotary-evaporated to dryness and water (50 mL) was added. The mixturewas adjusted to pH of 2-3 with 1 M dilute hydrochloric acid and whitesolids were precipitated. The solid was collected by filtration. Thecrude product was purified by column chromatography (petroleumether/ethyl acetate=10/1-0/1, TLC: petroleum ether/ethyl acetate=1/1) togive compound 4-13. LCMS m/z=562.1[M+H]⁺.

Step 13: Synthesis of Compound 4-14

Compound 4-13 (0.328 g, 583.55 μmol, 1 eq) and N,N-diisopropylethylamine(377.09 mg, 2.92 mmol, 508.21 μL, 5 eq) were dissolved indichloromethane (10 mL) and triflic anhydride (246.96 mg, 875.32 μmol,144.42 μL. 1.5 eq) was added at 0° C. The mixture was stirred at 0° C.for 1 hr. The mixture was combined with the 0.56 g batch for treatment.The mixture was poured into saturated aqueous ammonium chloride solution(50 mL), and extracted with ethyl acetate (20 mL×3 times). The organicphase was washed with saturated brine, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated to give a crudeproduct. The crude product was purified by column chromatography(petroleum ether/ethyl acetate=20/1-5/1, TLC: petroleum ether/ethylacetate=5/1) to give compound 4-14. ¹H NMR (400 MHz, CDCl3) δ=8.21-8.11(m, 1H), 8.00-7.90 (m, 1H), 5.86-5.69 (m, 1H), 5.25-5.09 (m, 1H),4.68-4.46 (m, 1H), 3.57-3.42 (m, 1H), 3.27-3.08 (m, 1H), 2.66-2.41 (m,6H), 1.79-1.67 (m, 9H), 1.21-1.07 (m, 9H); LCMS m/z=637.9[M-56+H]⁺,639.8[M-56+3H]⁺.

Step 14: Synthesis of Compound 4-15

Compound 4-14 (630 mg, 907.60 μmol, 1 eq) and compound 4-14A (420.90 mg,1.63 mmol, 1.8 eq, HCl) were dissolved in N,N-dimethylformamide (15 mL),and N,N-diisopropylethylamine (469.19 mg, 3.63 mmol, 632.33 μL, 4 eq)was added. The mixture was stirred at 20° C. for 2 hr. The mixture waspoured into water (30 mL), and extracted with ethyl acetate (20 mL×3).The organic phase was washed with saturated brine (10 mL), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentrated togive a crude product, which was purified by column chromatography(petroleum ether/ethyl acetate=50/1-1/1, TLC: petroleum ether/ethylacetate=0/1) to give compound 4-15. ¹H NMR (400 MHz, CDCl3) δ=8.18-8.05(m, 1H), 8.04-7.93 (m, 1H), 5.75-5.45 (m, 1H), 5.06-4.89 (m, 1H),4.66-4.35 (m, 1H), 4.19-3.84 (m, 3H), 3.82-3.45 (m, 1H), 3.43-3.12 (m,2H), 3.06-2.75 (m, 6H), 2.61-2.38 (m, 5H), 1.79-1.60 (m, 9H), 1.14-0.85(s, 9H); LCMS m/z=765.0[M+H]⁺.

Step 15: Synthesis of Compound 4-16

Compound 4-15 (400.00 mg, 522.71 μmol, 1 eq) was dissolved indichloromethane (8 mL), and m-chloroperoxybenzoic acid (200.00 mg,985.11 μmol, 85% mass content, 1.88 eq) was added. The mixture wasstirred at 20° C. for 2 hr. The mixture was combined with the 200 mgbatch for treatment. The reaction solution was washed with aqueoussodium sulfite (20 mL, 10%), dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated to give a crude product. Thecrude product was purified by column chromatography (SiO₂ 100 mesh,petroleum ether/ethyl acetate=50/1-1/1, TLC: petroleum ether/ethylacetate=2/1) to give compound 4-16. LCMS m/z=697.1[M-100+H]⁺.

Step 16: Synthesis of Compound 4-17

Compound 1-11A (57.79 mg, 501.73 μmol, 59.57 μL, 4 eq) was dissolved intoluene (1 mL), and sodium tert-butoxide (42.19 mg, 439.01 μmol, 3.5 eq)was added at 0° C. The mixture was stirred for 15 min. Then a solutionof compound 4-16 (100.00 mg, 125.43 μmol, 1 eq) in 0.1 mL toluene wasadded slowly to the reaction solution, and the mixture was reacted at 0°C. for 30 min. The reaction mixture was quenched with water (5 mL) andextracted with ethyl acetate (5 mL×2). The organic phases were combinedto give compound 4-17. LCMS m/z=636.1[M+H]⁺.

Step 17: Synthesis of Compound 4-18

Compound 4-17 (79.80 mg, 125.44 μmol, 1 eq) was dissolved indichloromethane (2 mL), and N,N-diisopropylethylamine (81.06 mg, 627.18μmol, 109.24 μL, 5 eq) was added at 18° C. The mixture was cooled downto −78° C. Acryloyl chloride (4.54 mg, 50.17 μmol, 4.09 μL, 0.4 eq) wasadded slowly to the reaction solution and the mixture was reacted at−78° C. for 0.5 hr. 8.00 mg of additional acryloyl chloride was added,and the mixture was reacted for another 1 hr. The reaction mixture wasquenched with saturated aqueous ammonium chloride (5 mL) and extractedwith dichloromethane (5 mL*2). The organic phases were combined. Thecrude product was added to potassium carbonate (1.7 M, 1 mL)/methanol (1mL) and the mixture was stirred at 18° C. for 1 hr. The product wasdetermined (time=0.943) to give compound 4-18. LCMS m/z=690.3 [M+H]⁺.

Step 18: Synthesis of Compounds 4A and 4B

Compound 4-18 (100 mg, 144.88 μmol, 1 eq) was dissolved indichloromethane (2 mL) and trifluoroacetic acid (3.08 g, 27.01 mmol,2.00 mL, 186.45 eq), and the mixture was reacted at 18° C. for 1 hr. Themixture was concentrated to give compound 4-19. The compound 4-19 waspurified by a high-performance liquid chromatography column (Column:Phenomenex luna C18 100*40 mm*5 μm; mobile phase: [H₂O(0.1%TFA)-acetonitrile]; acetonitrile %: 5%-30%, 8 min). To the sample wasadded 0.05 mL of dilute hydrochloric acid 0.2 mL. The mixture wasconcentrated under vacuum to give compound 4A hydrochloride(time-to-peak: 2.417 min, LCMS m/z=590.1 [M+H]+, 295.9[M/2+H]⁺) andcompound 4B hydrochloride (time-to-peak: 2.388 min, LCMS m/z=590.1[M+H]+, 295.9[M/2+H]⁺).

Example 5

Step 1: Synthesis of Compound 5-1

Tetrahydrofuran (27 mL) and sodium hydride (789.28 mg, 19.73 mmol, 60%mass content, 2 eq) were added to a pre-prepared clean reaction flask,and stirred. Then the mixture was cooled down to 0 to 5° C. and methylacetoacetate (2.29 g, 19.73 mmol, 2.12 mL, 2 eq) was added dropwise. Themixture was reacted for 30 min. Then n-butyllithium (2.5 M, 7.50 mL, 1.9eq) was added dropwise, and the mixture was reacted for another 30 min.The mixture was then cooled down to −70 to −65° C. A solution ofcompound 4-6 (2.75 g, 9.87 mmol, 1 eq) in tetrahydrofuran (27 mL) wasadded dropwise, and the mixture was reacted for another 0.5 hr. Thereaction solution was quenched by pouring into 50 mL of saturatedammonium chloride solution. The organic phase was dried with 1.50 g ofanhydrous sodium sulfate and filtered. The filtrate wasrotary-evaporated under reduced pressure at 45° C. The crude product waspurified by column chromatography (petroleum ether/ethylacetate=100/0-70/30, TLC: petroleum ether/ethyl acetate=1/1) to givecompound 5-1. ¹H NMR (400 MHz, CDCl₃) δ=8.40 (d, J=2.8 Hz, 1H), 7.41 (d,J=11.6 Hz, 1H), 5.95-5.91 (m, 1H), 5.69-5.64 (m, 1H), 4.04-3.98 (m, 1H),3.78-3.70 (m, 4H), 3.56 (d, J=0.8 Hz, 2H), 3.37 (d, J=3.2, 8.4 Hz, 1H),3.08-2.99 (m, 2H), 2.61-2.54 (m, 1H), 2.50 (s, 3H), 2.18-2.04 (m, 2H),1.81-1.70 (m, 2H). LCMS: MS m/z=395.0[M+H]⁺.

Step 2: Synthesis of Compound 5-2

Dichloromethane (25 mL) and compound 5-1 (1.6 g, 4.05 mmol, 1 eq) wereadded to a pre-prepared clean reaction flask and stirred. ThenN,N-dimethylformamide dimethyl acetal (724.30 mg, 6.08 mmol, 807.47 μL,1.5 eq) was added and the mixture was reacted at room temperature of 20°C. for 12 hr. Then the mixture was cooled down to 0 to 5° C. Borontrifluoride etherate (575.13 mg, 4.05 mmol, 500.11 μL, 1 eq) was added.The mixture was reacted at room temperature of 20° C. for another 1 hr.The reaction solution was rotary-evaporated under reduced pressure at30° C. to give compound 5-2, which was used directly in the next step.

Step 3: Synthesis of Compound 5-3

Tetrahydrofuran (58 mL) and compound 5-2 (3.9 g, 8.40 mmol, 87.233% masscontent, 1 eq) were added to a pre-prepared clean reaction flask andstirred. The mixture was cooled down to −70 to −65° C. and lithiumtri-sec-butylborohydride (1 M, 9.24 mL, 1.1 eq) was added dropwise. Themixture was reacted for 0.5 h. The reaction solution was poured into 50mL of saturated ammonium chloride solution. The organic phase was driedwith 2.00 g of anhydrous sodium sulfate and filtered. The filtrate wasrotary-evaporated under reduced pressure at 45° C. The crude product waspurified by column chromatography (petroleum ether/ethylacetate=100/0-70/30, TLC: petroleum ether/ethyl acetate=5/1) to givecompound 5-3. LCMS: MS m/z=407.0 [M+H]⁺

Step 4: Synthesis of Compound 5-4

Methanol (4 mL), compound 5-3 (0.65 g, 1.60 mmol, 1 eq), and methylisothiourea sulfate (1.22 g, 6.39 mmol, 4 eq, H₂SO₄) were added to apre-prepared reaction flask and stirred. Then sodium methoxide (172.61mg, 3.20 mmol, 2 eq) was added and the mixture was reacted at roomtemperature of 25° C. for 1 hr. After additional sodium methoxide(172.62 mg, 3.20 mmol, 2 eq) was added, the mixture was reacted foranother 15 hr. The reaction solution was rotary-evaporated under reducedpressure at 45° C. 10 mL of water was added to the obtained white solid,and the mixture was extracted with 10 mL of ethyl acetate. The layerswere separated. The organic phase was washed once with 10 mL ofsaturated brine, dried with 0.50 g of anhydrous sodium sulfate, andfiltered. The filtrate was rotary-evaporated under reduced pressure at45° C. The crude product was purified by column chromatography(petroleum ether/ethyl acetate=100/0-40/60, TLC: petroleum ether/ethylacetate=1/1) to give compound 5-4. LCMS: MS m/z=447.0[M+H]⁺.

Step 5: Synthesis of Compound 5-5

Dichloromethane (20 mL) and compound 5-4 (610 mg, 1.36 mmol, 1 eq) wereadded to a pre-prepared clean reaction flask and stirred. After themixture was cooled down to 0 to 5° C., N,N-diisopropylethylamine (617.36mg, 4.78 mmol, 832.02 μL, 3.5 eq) and triflic anhydride (770.13 mg, 2.73mmol, 450.37 μL, 2 eq) were added sequentially. The mixture was reactedfor 0.5 hr. The reaction solution was poured into 20 mL of saturatedammonium chloride solution, and then the layers were separated. Theorganic phase was washed once with 10 mL of saturated brine, dried withanhydrous sodium sulfate, and filtered. The filtrate wasrotary-evaporated under reduced pressure at 45° C. The crude product waspurified by column chromatography (petroleum ether/ethylacetate=100/0-70/30, TLC: petroleum ether/ethyl acetate=5/1) to givecompound 5-5. 1H NMR (400 MHz, CDCl₃) δ=8.26 (d, J=5.2 Hz, 1H), 7.48 (d,J=14.4 Hz, 1H), 5.73-5.67 (m, 1H), 5.53-5.49 (m, 1H), 5.15 (dd, J=3.2,15.6 Hz, 1H), 4.88 (d, J=15.6 Hz, 1H), 4.06-3.99 (m, 1H), 3.80-3.72 (m,1H), 3.30-3.25 (m, 1H), 3.12-3.04 (m, 1H), 2.61-2.49 (m, 7H), 2.19-2.07(m, 2H), 1.83-1.68 (m, 3H).

Step 6: Synthesis of Compound 5-6

N,N-dimethylformamide (5 mL) and compound 5-5 (0.33 g, 569.94 μmol, 1eq) were added to a pre-prepared clean reaction flask and stirred. ThenN,N-diisopropylethylamine (368.29 mg, 2.85 mmol, 496.35 μL, 5 eq) andcompound 5-5a (143 mg., 1.14 mmol, 2.00 eq, 2HCl) was addedsequentially. The mixture was heated to 100° C. and reacted for 1 hr.The reaction solution was poured into 20 mL of saturated ammoniumchloride solution and the mixture was then added to 10 mL of ethylacetate. The layers were separated. The organic phase was dried withanhydrous sodium sulfate, and filtered. The filtrate wasrotary-evaporated under reduced pressure at 45° C. The crude product waspurified by column chromatography (dichloromethane/methanol=100/0-85/15,TLC: dichloromethane/methanol=15/1) to give compound 5-6. ¹H NMR (400MHz, CDCl₃) δ=8.22 (d, J=4.4 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 5.71-5.66(m, 1H), 5.57-5.53 (m, 1H), 4.89-4.80 (m, 2H), 4.05-3.86 (m, 2H),3.77-3.32 (m, 1H), 3.60-3.57 (m, 1H), 3.39-3.38 (m, 1H), 3.31-3.26 (m,1H), 3.23-3.17 (m, 1H), 3.12-3.09 (m, 1H), 3.02-2.96 (m, 3H), 2.93-2.83(m, 2H), 2.57-2.56 (m, 1H), 2.54-2.52 (m, 7H), 2.16-2.04 (m, 2H),1.79-1.71 (m, 3H). LCMS: MS m/z=554.0[M+H]⁺.

Step 7: Synthesis of Compound 5-7

Compound 5-6 (190 mg, 342.90 μmol, 1 eq) was dissolved intetrahydrofuran (2 mL), and stirred. Then the mixture was cooled down to0 to 5° C., and trifluoroacetic anhydride (108.03 mg, 514.34 μmol, 71.54μL, 1.5 eq) and triethylamine (121.44 mg, 1.20 mmol, 167.04 μL, 3.5 eq)were added. The mixture was reacted for 0.5 h. The reaction solution waspoured into 10 mL of saturated ammonium chloride solution, and thenextracted with 10 mL dichloromethane. The organic phase was washed oncewith saturated brine, dried with anhydrous sodium sulfate, and filtered.The filtrate was rotary-evaporated under reduced pressure at 45° C. togive compound 5-7. LCMS: MS m/z=650.2[M+H]⁺.

Step 8: Synthesis of Compound 5-8

Dichloromethane (5 mL) and compound 5-7 (0.2 g, 290.04 μmol, 94.281%mass content, 1 eq) were added to a pre-prepared clean reaction flaskand stirred. Then m-chloroperoxybenzoic acid (143.96 mg, 667.37 μmol,80% mass content, 2.30 eq) was added and the mixture was reacted at roomtemperature of 25° C. for 0.5 h. The reaction solution was poured into20 mL of sodium thiosulfate solution (10%), and the mixture wasextracted with 15 mL of dichloromethane. The organic phase was driedwith anhydrous sodium sulfate, and filtered. The filtrate wasrotary-evaporated under reduced pressure at 45° C. The crude product waspurified by column chromatography (dichloromethane/methanol=100/0-85/15,TLC: dichloromethane/methanol=15/1) to give compound 5-8. LCMS: MSm/z=682.0[M+H]⁺

Step 9: Synthesis of Compound 5-9

Toluene (5 mL) and compound 1-11A (148.59 mg, 1.29 mmol, 153.18 μL, 4eq) were added to a pre-prepared clean reaction flask and stirred. Thenthe mixture was cooled down to 0 to 5° C. and sodium tert-butoxide(123.98 mg, 1.29 mmol, 4 eq) was added. The mixture was reacted for 15min. A solution of compound 5-8 (0.22 g, 322.53 μmol, 1 eq) in 0.2 mL oftoluene was quickly added, and the mixture was reacted for 0.5 hr. Thereaction solution was poured into 10 mL of saturated ammonium chloridesolution, and the mixture was extracted with 10 mL of dichloromethane.The organic phase was washed once with 10 mL of saturated brine, driedwith 0.50 g of anhydrous sodium sulfate, and filtered. The filtrate wasrotary-evaporated under reduced pressure at 45° C. to give compound 5-9.LCMS: MS m/z=621.4 [M+H]⁺

Step 10: Synthesis of Compound 5-10

Dichloromethane (5 mL) and compound 5-9 (98.26 mg, 125.80 μmol, 79.529%mass content, 1 eq) were added to a pre-prepared reaction flask andstirred. The mixture was then cooled down to −60° C. andN,N-diisopropylethylamine (162.59 mg, 1.26 mmol, 219.12 μL, 10 eq) wasadded. A solution of acryloyl chloride (17.08 mg, 188.70 μmol, 15.39 μL,1.5 eq) in 0.3 mL of dichloromethane was added dropwise, and the mixturewas reacted for 10 min. The reaction solution was poured into 5 mL ofsaturated ammonium chloride solution and the layers were separated. Theorganic phase was washed once with 5 mL of saturated brine, dried withanhydrous sodium sulfate, and filtered. The filtrate wasrotary-evaporated under reduced pressure at 35° C. to give compound5-10, which was used directly in the next step. LCMS: MS m/z=675.1[M+H]⁺

Step 11: Synthesis of Compounds 5A and 5B

Dichloromethane/trifluoroacetic acid (4 mL, 5/3) and compound 5-10 (0.1g, 148.10 μmol, 1 eq) were added to a reaction flask and the mixture wasreacted at room temperature of 25° C. for 0.5 h. The reaction solutionwas slowly added dropwise to 15 mL of saturated sodium bicarbonatesolution, and then the mixture was extracted with 10 mL ofdichloromethane. The organic phase was washed once with 10 mL ofsaturated brine, dried with anhydrous sodium sulfate, and filtered. Thefiltrate was rotary-evaporated under reduced pressure at 30° C. Thecrude product was purified by a high-performance liquid chromatographycolumn (Column: Phenomenex Gemini-NX 150*30 mm*5 μm; mobile phase:[H₂O(0.1% TFA)-acetonitrile]; acetonitrile %: 20%-50%, 9 min) to givecompound 5-11. Compound 5-11 was resolved by SFC (DAICEL CHIRALPAK AS(250 mm*30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O EtOH]; ethanol:50%-50%, 15 min).

5A was obtained (time-to-peak in chiral column: 1.516). SFC resolutionmethod (column: Chiralpak AD-3, 50×4.6 mm, I.D., 3 μm; Mobile phase: A(CO2) and B (isopropanol, containing 0.05% diethanolamine); Gradient: B%=5-50%, 3 min; Flow rate: 3.4 mL/min; Wavelength: 220 nm; Pressure:1800 psi. Optical purity: 91.04%. ¹H NMR (400 MHz, CDCl₃) δ=8.26 (s,1H), 7.37 (s, 1H), 6.62-6.56 (m, 1H), 6.42-6.38 (m, 1H), 5.84 (d, J=11.6Hz, 1H), 5.58 (dd, J=4.0, 11.2 Hz, 1H), 4.94 (s, 2H), 4.55-4.43 (m, 1H),4.27-4.18 (m, 1H), 4.02-3.87 (m, 1H), 3.76-3.73 (m, 1H), 3.23-3.18 (m,4H), 3.07-2.98 (m, 2H), 2.87-2.74 (m, 3H), 2.56-2.53 (m, 6H), 2.13-2.07(m, 1H), 1.82-1.76 (m, 3H), 1.37-1.29 (m, 3H). LCMS: MS m/z=591.2[M+H]⁺.

5B was obtained (time-to-peak in chiral column: 1.800). SFC resolutionmethod (column: Chiralpak AD-3, 50×4.6 mm, I.D., 3 μm; Mobile phase: A(CO2) and B (isopropanol, containing 0.05% diethanolamine); Gradient: B%=5-50%, 3 min; Flow rate: 3.4 mL/min; Wavelength: 220 nm; Pressure:1800 psi. Optical purity: 99.74%. ¹H NMR (400 MHz, CDCl₃) δ=8.31 (s,1H), 7.36 (s, 1H), 6.63-6.53 (m, 1H), 6.42-6.37 (m, 1H), 5.83 (d, J=11.6Hz, 1H), 5.59 (dd, J=4.0, 11.2 Hz, 1H), 4.98-4.88 (m, 2H), 4.55-4.80 (m,1H), 4.24-4.19 (m, 1H), 4.01-3.97 (m, 1H), 3.93-3.85 (m, 1H), 3.74-3.69(m, 1H), 3.56-3.52 (m, 1H), 3.28-3.05 (m, 3H), 3.03-2.95 (m, 1H),2.83-2.69 (m, 3H), 2.58-2.53 (m, 6H), 2.43-2.33 (m, 1H), 2.12-2.06 (m,1H), 1.91-1.86 (m, 1H), 1.81-1.79 (m, 2H), 1.45-1.30 (m, 2H). LCMS: MSm/z=591.2[M+H]⁺.

Example 6

Step 1: Synthesis of Compound 6-1

Compound 4-17 (190 mg, 298.65 μmol, 1 eq) and N,N-diisopropylethylamine(192.99 mg, 1.49 mmol, 260.10 μL, 5 eq) were dissolved indichloromethane (5 mL), and trifluoroacetic anhydride (94.09 mg, 447.98μmol, 62.31 μL, 1.5 eq) was added at 0° C. The mixture was reacted at 0°C. for 0.5 hr. The reaction mixture was quenched with saturated aqueousammonium chloride (5 mL), and extracted with dichloromethane (5 mL*2).The organic phases were combined, dried over anhydrous sodium sulfate,and filtered. The filtrate was concentrated to give compound 6-1. LCMS:MS m/z=732.3[M+H]⁺

Step 2: Synthesis of Compound 6-2

Compound 6-1 (200 mg, 273.15 μmol, 1 eq) was dissolved indichloromethane (4 mL), and trifluoroacetic acid (3.08 g, 27.01 mmol, 2mL, 98.89 eq) was added at 0° C. The mixture was reacted at 18° C. for0.5 hr. The mixture was directly rotary-evaporated to dryness to give acrude product, which was purified by a high-performance liquidchromatography column (Phenomenex Gemini-NX 150*30 mm*5 μm; mobilephase: [H₂O(0.1% TFA)-acetonitrile]; acetonitrile %: 30%-60%, 9 min) togive compound 6-2. LCMS: MS m/z=632.3[M+H]⁺

Step 3: Synthesis of Compound 6-3

Compound 6-2 (110 mg, 174.03 μmol, 1 eq) and paraformaldehyde (88.91 mg,1.74 mmol, 10 eq) were dissolved in 1,2-dichloroethane (1 mL) andmethanol (1 mL). Glacial acetic acid (1.05 mg, 17.40 μmol, 9.95e-1 μL,0.1 eq) was added and the mixture was stirred for 30 min. Sodiumcyanoborohydride (21.87 mg, 348.06 μmol, 2 eq) was added and the mixturewas stirred at 25° C. for 10 hr. The mixture was poured into saturatedaqueous ammonium chloride (10 mL), and dichloromethane (5 mL×3) wasadded. The organic phase was dried over anhydrous sodium sulfate,filtered and concentrated to give compound 6-3. LCMS: MS m/z=646.1[M+H]⁺, 647.7 [M+2H]⁺

Step 4: Synthesis of Compound 6-4

Compound 6-3 (90 mg, 139.30 μmol, 1 eq) was dissolved in methanol (3mL), and potassium carbonate (1.7 M, 2.70 mL, 32.95 eq) was added. Themixture was reacted at 18° C. for 1 hr. The reaction mixture wasquenched with saturated aqueous ammonium chloride (5 mL), and extractedwith ethyl acetate (5 mL×2). The organic phases were combined, washedwith saturated brine, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated to give compound 6-4. LCMS: MSm/z=550.2[M+H]⁺, 551.8[M+2H]⁺.

Step 5: Synthesis of Compounds 6A and 6B

Compound 6-4 (76 mg, 138.16 μmol, 1 eq) was dissolved in dichloromethane(20 mL), and N,N-diisopropylethylamine (267.83 mg, 2.07 mmol, 360.96 μL,15 eq) was added. Acryloyl chloride (12.50 mg, 138.16 μmol, 11.27 μL, 1eq) was added at −60° C. The mixture was reacted at −60° C. for 0.5 hr.The mixture was quenched with saturated aqueous ammonium chloride (5mL), and extracted with ethyl acetate (5 mL×2). The organic phases werecombined and concentrated to give compound 6-5, which was purified by ahigh-performance liquid chromatography column (Column: PhenomenexGemini-NX C18 75*30 mm*3 μm; mobile phase: [H₂O(0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; acetonitrile %: 25%-55%, 6 min) to give compound 6-5,which was isolated by SFC (column: Phenomenex Gemini-NX C18 75*30 mm*3μm; mobile phase: [H₂O(0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; acetonitrile %:25%-55%, 6 min) to give compound 6A ((time-to-peak in chiralcolumn=1.435 min), SFC analysis method (column: Chiralpak AD-3, 50×4.6mm, I.D., 3 μm; Mobile phase: A (CO2) and B (isopropanol, containing0.05% diethanolamine); Gradient: B %=5-50%, 3 min; Flow rate: 3.4mL/min; Wavelength: 220 nm; Pressure: 1800 psi. Optical purity: 87.38%.LCMS: MS m/z=604.1[M+H]+) and compound 6B ((time-to-peak in chiralcolumn=1.643), SFC analysis method (column: Chiralpak AD-3, 50×4.6 mm,I.D., 3 μm; Mobile phase: A (CO2) and B (isopropanol, containing 0.05%diethanolamine); Gradient: B %=5-50%, 3 min; Flow rate: 3.4 mL/min;Wavelength: 220 nm; Pressure: 1800 psi. Optical purity: 100%. LCMS: MSm/z=604.1 [M+H]+).

Example 7

Step 1: Synthesis of Compound 7-1

N,N-dimethylformamide (6 mL) and compound 5-9 (150 mg, 193.18 μmol, 80%mass content, 1 eq) were added to a pre-prepared reaction flask, andstirred. The mixture was then cooled down to 0 to 5° C. Then2-fluoroacrylic acid (26.10 mg, 289.78 μmol, 3.08 μL, 1.5 eq),2-(7-azabenzotriazol)-N,N,N,N-tetramethyluronium hexafluorophosphate(110.18 mg, 289.78 μmol, 1.5 eq), and N,N-diisopropylethylamine (74.90mg, 579.55 μmol, 100.94 μL, 3 eq) were added sequentially and themixture was reacted for 0.5 h. The reaction solution was poured into 15mL of saturated ammonium chloride solution, and extracted with 20 mL ofethyl acetate. The aqueous phase was washed once with 15 mL of ethylacetate. The organic phases were combined and washed once with 15 mL ofsaturated brine, then dried with anhydrous sodium sulfate, and filtered.The filtrate was rotary-evaporated under reduced pressure at 45° C. Thecrude product was purified by column chromatography(dichloromethane/methanol=50/1, 30/1, 20/1, 15/1, 10/1, TLC:dichloromethane/methanol=10/1) to give compound 7-1. ¹H NMR (400 MHz,CDCl3) δ=8.24-8.21 (m, 1H), 7.48-7.43 (m, 1H), 5.71-5.65 (m, 1H),5.61-5.55 (m, 1H), 5.27-5.23 (m, 1H), 4.97-4.84 (m, 2H), 4.60-4.56 (m,2H), 4.06-4.00 (m, 2H), 3.76-3.67 (m, 5H), 3.57-3.37 (m, 2H), 3.21-3.15(m, 4H), 3.04-2.97 (m, 4H), 2.93-2.81 (m, 3H), 2.54 (s, 3H), 2.38-2.33(m, 1H), 2.19-2.05 (m, 6H), 1.79-1.66 (m, 3H). LCMS: MS m/z=693.2[M+H]⁺.

Step 2: Synthesis of Compounds 7A and 7B

Dichloromethane/trifluoroacetic acid (7 mL, 5/3) and compound 7-1 (70mg, 100.98 μmol, 1 eq) were added to a reaction flask and the mixturewas reacted at room temperature of 25° C. for 3 hr. The reactionsolution was slowly added dropwise to 15 mL of saturated sodiumbicarbonate solution and then mixed with a small-scale reactionsolution. The mixture was extracted with 10 mL of dichloromethane. Theorganic phase was washed once with 10 mL of saturated brine, dried withanhydrous sodium sulfate, and filtered. The filtrate wasrotary-evaporated under reduced pressure at 30° C. to give a crudeproduct, which was purified by a high-performance liquid chromatographycolumn (column: Phenomenex lμna C18 100*40 mm*5 μm; mobile phase:[H₂O(0.1% TFA)-acetonitrile]; acetonitrile %: 10%-35%, 8 min) to givecompound 7-2, which was isolated by SFC (column: DAICEL CHIRALCEL OJ(250 mm*30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O EtOH]; EtOH %:40%-40%, 15 min).

Compound 7A was obtained (time-to-peak in chiral column: 1.263 min). SFCresolution method (column: Chiralcel OJ-3, 50×4.6 mm I.D., 3 μm; Mobilephase: A (CO2) and B (ethanol, containing 0.05% diisopropylamine);Gradient: B %=5-50%, 3 min; Flow rate: 3.4 mL/min; Wavelength: 220 nm;Pressure: 1800 psi. Optical purity: 91.94%. ¹HNMR (400 MHz, CDCl₃)δ=8.29 (s, 1H), 7.35 (s, 1H), 5.61-5.57 (m, 1H), 5.48-5.32 (m, 1H),5.28-5.24 (m, 1H), 4.95-4.86 (m, 3H), 4.44-4.43 (m, 1H), 4.20-4.16 (m,2H), 3.97-3.93 (m, 1H), 3.80-3.78 (m, 1H), 3.50-3.48 (m, 1H), 3.27-3.22(m, 1H), 3.14-2.95 (m, 4H), 2.81-2.71 (m, 3H), 2.52-2.50 (m, 7H),2.34-2.28 (m, 1H), 2.08-2.02 (m, 1H), 1.91-1.84 (m, 2H). LCMS: MSm/z=609.2[M+H]⁺.

Compound 7B was obtained (time-to-peak in chiral column: 1.393 min). SFCresolution method (column: Chiralcel OJ-3, 50×4.6 mm I.D., 3 μm; Mobilephase: A (CO2) and B (ethanol, containing 0.05% diisopropylamine);Gradient: B %=5-50%, 3 min; Flow rate: 3.4 mL/min; Wavelength: 220 nm;Pressure: 1800 psi. Optical purity: 82.48%. ¹HNMR (400 MHz, CDCl3)δ=8.26 (s, 1H), 7.35 (s, 1H), 5.59-5.55 (m, 1H), 5.48-5.36 (m, 1H),5.29-5.24 (m, 1H), 4.93 (s, 2H), 4.42-4.40 (m, 1H), 4.24-4.20 (m, 2H),3.73-3.70 (m, 1H), 3.24-2.98 (m, 8H), 2.90-2.71 (m, 3H), 2.53-2.48 (m,7H), 2.33-2.31 (m, 1H), 2.09-2.04 (m, 1H), 1.89-1.85 (m, 2H). LCMS: MSm/z=609.1 [M+H]⁺.

Example 8

Step 1: Synthesis of Compound 8-2

In a dry 2 L three-necked flask (in anhydrous and oxygen-freeenvironment), sodium hydride (39.12 g, 978.08 mmol, 60% mass content,2.4 eq) was added to N,N-dimethylformamide (510 mL) and the reactionsystem became non-homogeneous and gray. The mixture was cooled down to0° C., and a solution of compound 8-1 (51 g, 407.53 mmol, 1 eq) inN,N-dimethylformamide (200 mL) was added dropwise under nitrogen. Themixture was reacted at 0° C. for 0.5 hr. p-Methoxybenzyl chloride(140.41 g, 896.57 mmol, 122.10 mL, 2.2 eq) was added and the reactionsystem was slowly warmed up to 20° C. The reaction system became earthyred and reacted under nitrogen for 7.5 hr. The reaction solution wasslowly added to 200 mL of saturated ammonium chloride, and extractedwith methyl tert-butyl ether (200 mL×2). The organic phases werecombined, washed with 200 mL of saturated brine, dried with anhydroussodium sulfate, and filtered. The filtrate was then concentrated to givea crude product. The crude product was separated by chromatographypurification system COMBI-FLASH (gradient elution: petroleum ether:ethylacetate=10:0-10:1, petroleum ether:ethyl acetate=10:1) to give compound8-2. ¹H NMR (400 MHz, CDCl3) δ=7.23-7.18 (m, 4H), 6.91-6.87 (m, 1H),6.82-6.76 (m, 4H), 6.65-6.59 (m, 2H), 4.20 (s, 4H), 3.79 (s, 6H), 2.19(s, 3H). LCMS: MS m/z=366.1 [M+H]⁺.

Step 2: Synthesis of Compound 8-3

2,2,6,6-tetramethylpiperidine (31.31 g, 221.65 mmol, 37.63 mL, 3 eq) wasadded to anhydrous tetrahydrofuran (300 mL), and the mixture was cooleddown to −5° C. n-Butyllithium (2.5 M, 94.57 mL, 3.2 eq) was addeddropwise, and the mixture was reacted at −5 to 0° C. for 15 min. Themixture was cooled down to −60° C., and a solution of compound 8-2 (27g, 73.88 mmol, 1 eq) in tetrahydrofuran (60 mL) was added. The mixturewas reacted at −60° C. for 0.5 h. N,N-dimethylformamide (108.00 g, 1.48mol, 113.69 mL, 20 eq) was added rapidly and the mixture was reacted at−60° C. for 10 min. 400 mL of saturated ammonium chloride was added tothe reaction solution and the mixture was extracted with 200 mL×2 ofmethyl tert-butyl ether. The organic phases were combined, washed with200 mL of saturated brine, dried with anhydrous sodium sulfate, andfiltered. The filtrate was concentrated to give a crude product, whichwas slurried with 70 mL of a solvent mixture of petroleum ether andmethyl tert-butyl ether (petroleum ether:methyl tert-butyl ether=5:1)for 0.5 hr, and then filtered. The filter cake was rotary-evaporated todryness, and the filtrate was stirred and purified by column (petroleumether:ethyl acetate=100:0-10:1) to give compound 8-3. ¹H NMR (400 MHz,CDCl₃) δ=10.43-10.35 (m, 1H), 7.21-7.18 (m, 5H), 6.92-6.81 (m, 5H), 4.25(s, 4H), 3.80 (s, 6H), 2.23 (s, 3H). LCMS: MS m/z=394.2[M+H]⁺.

Step 3: Synthesis of Compound 8-4

Compound 8-3 (17.8 g, 45.24 mmol, 1 eq) was added toN,N-dimethylformamide (170 mL). Bromosuccinimide (8.05 g, 45.24 mmol, 1eq) was added and the mixture was reacted at 20° C. for 20 min. Thereaction solution was added to 300 mL of water, and extracted with 150mL×2 of methyl tert-butyl ether. The organic phases were combined,washed with 100 mL×2 of saturated brine, dried with anhydrous sodiumsulfate, and filtered. The filtrate was concentrated. The crude productwas slurried with a solvent mixture of ethyl acetate and methyltert-butyl ether (ethyl acetate:methyl tert-butyl ether=1:1) for 0.5 hr,and then filtered. The filter cake was rotary-evaporated to dryness togive compound 8-4. ¹H NMR (400 MHz, CDCl₃) δ=10.39 (s, 1H), 7.17 (d,J=8.8 Hz, 4H), 6.89 (d, J=8.8 Hz, 1H), 6.85-6.82 (m, 4H), 4.22 (s, 4H),3.79 (s, 6H), 2.28 (s, 3H). LCMS: MS m/z=472.1[M+H]⁺, 474.1[M+3H]⁺.

Step 4: Synthesis of Compound 8-5

Compound 8-4 (19.3 g, 40.86 mmol, 1 eq) was added toN,N-dimethylformamide (190 mL). Cuprous iodide (15.56 g, 81.72 mmol, 2eq) and methyl fluorosulfonyldifluoroacetate (39.25 g, 204.30 mmol,25.99 mL, 5 eq) were added, and the mixture was reacted at 100° C. undernitrogen for 1 hr. The reaction solution was filtered through a pad ofdiatomaceous earth. The filtrate was added to 300 mL of water, andextracted with 150 mL×2 of methyl tert-butyl ether. The organic phaseswere combined, washed with saturated brine (200 mL×2), dried withanhydrous sodium sulfate, and filtered. The filtrate was concentrated.The crude product was purified by column (petroleum ether:ethylacetate=100:0-10:1, petroleum ether:ethyl acetate=5:1) to give compound8-5. ¹H NMR (400 MHz, CDCl₃) δ=10.37 (q, J=4.0 Hz, 1H), 7.18-7.11 (m,4H), 6.89-6.82 (m, 4H), 6.73 (d, J=8.8 Hz, 1H), 4.36 (s, 4H), 3.81 (s,6H), 2.37-2.29 (m, 3H). LCMS: MS m/z=484.0[M+Na]⁺.

Step 5: Synthesis of Compound 8-6

Anhydrous tetrahydrofuran (50 mL) and sodium hydride (1.17 g, 29.26mmol, 60% mass content, 3 eq) were added to a dry three-necked flask.The mixture was cooled down to 0° C. Methyl acetoacetate (3.40 g, 29.26mmol, 3.15 mL, 3 eq) was added dropwise under nitrogen and the mixturewas reacted at 0° C. under nitrogen for 0.5 hr. n-Butyllithium (2.5 M,11.70 mL, 3 eq) was added dropwise, and the mixture was reacted at 0° C.for 0.5 hr. The mixture was cooled down to −60° C. A solution ofcompound 8-5 (4.5 g, 9.75 mmol, 1 eq) in tetrahydrofuran (20 mL) wasadded dropwise, and the mixture was reacted at −60° C. for 0.5 hr. 100mL of saturated ammonium chloride solution was added to the reactionsolution, and the mixture was extracted with 30 mL of ethyl acetate. Theorganic phase was washed with 80 mL of saturated brine, dried withanhydrous sodium sulfate, and filtered. The filtrate was concentrated togive a crude product, which was combined and purified by column(petroleum ether:ethyl acetate=100:0-3:1, petroleum ether:ethylacetate=3:1) to give compound 8-6 as a yellow oil. ¹H NMR (400 MHz,CDCl3) δ=7.18-7.15 (m, 4H), 6.90-6.78 (m, 4H), 6.61 (d, J=8.8 Hz, 1H),5.72-5.57 (m, 1H), 4.31 (m, 4H), 3.81 (s, 6H), 3.76 (s, 3H), 3.56 (s,2H), 3.50-3.38 (m, 1H), 2.98-2.93 (m, 1H), 2.38-2.26 (m, 3H). LCMS: MSm/z=578.1[M+H]⁺.

Step 6: Synthesis of Compound 8-7

Compound 8-6 (3 g, 5.19 mmol, 1 eq) was added to anhydrousdichloromethane (30 mL), and N,N-dimethylformamide dimethyl acetal(742.74 mg, 6.23 mmol, 828.02 μL, 1.2 eq) was added. The mixture wasreacted at 20° C. for 16 hr. Boron trifluoride etherate (884.66 mg, 6.23mmol, 769.27 μL, 1.2 eq) was added, and the mixture was reacted at 20°C. for 1 hr. The reaction solution was added to 20 mL of saturatedsodium bicarbonate solution. The layers were separated, and the aqueousphase was extracted with 20 mL of dichloromethane. The organic phaseswere combined, dried with anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated. The crude product was purified by column(petroleum ether:ethyl acetate=100:0-3:1, petroleum ether:ethylacetate=3:1) to give compound 8-7. ¹H NMR (400 MHz, CDCl₃) δ=8.43 (d,J=0.8 Hz, 1H), 7.21-7.10 (m, 4H), 6.91-6.81 (m, 4H), 6.70 (d, J=8.8 Hz,1H), 5.93 (dd, J=3.2, 14.8 Hz, 1H), 4.35 (s, 4H), 3.8 (s, 3H), 3.81 (s,6H), 3.38-3.29 (m, 1H), 2.68 (dd, J=3.6, 16.8 Hz, 1H), 2.39-2.24 (m,3H). LCMS: MS m/z=588.2[M+H]⁺.

Step 7: Synthesis of Compound 8-8

Compound 8-7 (2.1 g, 3.57 mmol, 1 eq) was added to anhydroustetrahydrofuran (21 mL). The mixture was cooled down to −60° C., andlithium tri-sec-butylborohydride (1 M, 4.29 mL, 1.2 eq) was added undernitrogen. The mixture was reacted at −60° C. for 0.5 hr. The reactionsolution was added to 30 mL of saturated ammonium chloride. The layerswere separated after extraction. The organic phase was washed with 20 mLof saturated brine, dried with anhydrous sodium sulfate, and filtered.The filtrate was concentrated to give a crude product, which waspurified by column (petroleum ether:ethyl acetate=100:0-3:1, petroleumether:ethyl acetate=3:1) to give compound 8-8. ¹H NMR (400 MHz, CDCl3)δ=7.167-7.14 (m, 4H), 6.87-6.83 (m, 4H), 6.63 (d, J=8.8 Hz, 1H),5.05-5.00 (m, 1H), 4.61-4.58 (m, 1H), 4.42-4.24 (m, 5H), 3.85-3.73 (m,10H), 3.13-3.05 (m, 1H), 2.47-2.38 (m, 1H), 2.35-2.31 (m, 3H). LCMS: MSm/z=600.1 [M+H]⁺,

Step 8: Synthesis of Compound 8-9

Compound 8-8 (1.27 g, 2.15 mmol, 1 eq) was added to ethanol (15 mL) andwater (3 mL), and sodium bicarbonate (3.62 g, 43.08 mmol, 1.68 mL, 20eq) and methyl isothiourea sulfate (4.05 g, 21.54 mmol, 10 eq) wereadded. The mixture was reacted at 50° C. for 4 hr. The reaction solutionwas added to 40 mL of water, and extracted with 20 mL×2 of ethylacetate. The organic phases were combined, washed with 20 mL×2 ofsaturated brine, dried with anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated. The crude product was purified by column(petroleum ether:ethyl acetate=100:0-1:1, petroleum ether:ethylacetate=1:1) to give compound 8-9. ¹H NMR (400 MHz, CDCl3) δ=7.22-7.14(m, 4H), 6.91-6.82 (m, 4H), 6.65 (dd, J=8.4 Hz 1H), 5.12-5.08 (m, 1H),4.97-4.91 (m, 1H), 4.67-4.57 (m, 1H), 4.45-4.22 (m, 4H), 3.88-3.74 (m,6H), 3.43-3.35 (m, 1H), 2.77-2.72 (m, 1H), 2.59 (m, 3H), 2.40-2.31 (m,3H). LCMS: MS m/z=630.2[M+H]⁺.

Step 9: Synthesis of Compound 8-10

Compound 8-9 (0.57 g, 905.25 μmol, 1 eq) was added to anhydrousdichloromethane (6 mL), and N,N-diisopropylethylamine (409.48 mg, 3.17mmol, 551.86 μL, 3.5 eq) and triflic anhydride (510.81 mg, 1.81 mmol,298.72 μL, 2 eq) were added at 0° C. The mixture was reacted at 0 to 5°C. for 5 hr. The reaction solution was added to 20 mL of saturatedammonium chloride, and extracted with 10 mL of dichloromethane. Theorganic phase was dried with anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated. The crude product was purified by column(petroleum ether:ethyl acetate=100:0-5:1, petroleum ether:ethylacetate=3:1) to give compound 8-10. ¹H NMR (400 MHz, CDCl3) δ=7.21-7.11(m, 4H), 6.90-6.80 (m, 4H), 6.66 (d, J=8.4 Hz, 1H), 5.19-5.15 (m, 1H),5.04-4.93 (m, 1H), 4.77-4.72 (m, 1H), 4.41-4.19 (m, 4H), 3.80 (s, 6H),3.62-3.54 (m, 1H), 3.11-2.97 (m, 1H), 2.56 (s, 3H), 2.42-2.31 (m, 3H).LCMS: MS m/z=762.2[M+H]⁺.

Step 10: Synthesis of Compound 8-11

Compound 8-10 (0.45 g, 590.76 μmol, 1 eq) was added toN,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (229.05 mg,1.77 mmol, 308.69 μL, 3 eq) and compound 1-10A (306.37 mg, 1.18 mmol, 2eq, HCl) were added sequentially. The mixture was reacted at 50° C. for2 hr. The reaction solution was poured into 20 mL of water, andfiltered. The filter cake was dissolved in 20 mL of methyl tert-butylether, and washed with 20 mL of saturated brine. The organic phase wasdried with anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated to give compound 8-11. ¹H NMR (400 MHz, CDCl3) δ=7.44-7.32(m, 5H), 7.16-7.13 (m, 4H), 6.85-6.82 (m, 4H), 6.63 (d, J=7.6 Hz, 1H),5.21-5.15 (m, 2H), 4.80-4.66 (m, 3H), 4.39-4.22 (m, 4H), 3.93-3.88 (m,1H), 3.80 (s, 6H), 3.71-3.55 (m, 1H), 3.52-3.29 (m, 2H), 3.25-3.08 (m,3H), 3.06-2.96 (m, 2H), 2.91-2.77 (m, 1H), 2.71-2.68 (m, 1H), 2.52 (s,3H), 2.35-2.30 (m, 3H). LCMS: MS m/z=871.4[M+H]⁺.

Step 11: Synthesis of Compound 8-12

Compound 8-11 (580.00 mg, 665.94 μmol, 1 eq) was added to anhydrousdichloromethane (6 mL), and m-chloroperoxybenzoic acid (359.13 mg, 1.66mmol, 80% mass content, 2.5 eq) was added. The mixture was reacted at25° C. for 0.5 hr. The reaction solution was poured into 20 mL of sodiumthiosulfate solution (10%), and extracted with 10 mL of dichloromethane.The organic phase was dried with anhydrous sodium sulfate, and filtered.The filtrate was rotary-evaporated under reduced pressure at 45° C. Thecrude product was purified by column (petroleum ether:ethylacetate=100:0-1:1, petroleum ether:ethyl acetate=1:1) to give compound8-12. ¹H NMR (400 MHz, CDCl3) δ=7.40-7.37 (m, 5H), 7.17-7.12 (m, 4H),6.86-6.82 (m, 4H), 6.67-6.64 (d, J=8.4 Hz, 1H), 5.19 (s, 2H), 4.86-4.79(m, 2H), 4.71-4.63 (m, 1H), 4.35-4.24 (m, 4H), 3.82-3.81 (m, 1H), 3.80(s, 6H), 3.64-3.50 (m, 2H), 3.46-3.33 (m, 2H), 3.30-3.27 (m, 4H),3.25-3.11 (m, 3H), 2.71-2.65 (m, 1H), 2.52-2.45 (m, 1H), 2.38-2.30 (m,3H). LCMS: MS m/z=903.3[M+H]⁺.

Step 12: Synthesis of Compound 8-13

Compound 1-11A (117.35 mg, 1.02 mmol, 120.98 μL, 4 eq) was added todioxane (5 mL). The mixture was cooled down to 0-5° C. Sodiumtert-butoxide (97.91 mg, 1.02 mmol, 4 eq) was added and the mixture wasreacted for 10 min. A solution of compound 8-12 (230.00 mg, 254.72 μmol,1 eq) in toluene (1 mL) was added and the mixture was reacted for 0.5hr. The reaction solution was added to 20 mL of saturated ammoniumchloride, and extracted with 10 mL×2 of ethyl acetate. The organicphases were combined, washed with 20 mL of saturated brine, dried withanhydrous sodium sulfate, and filtered. The filtrate was concentrated.The crude product was purified by column (petroleum ether:ethylacetate=1:1-0:1, dichloromethane:methanol=100:0-10:1,dichloromethane:methanol=10:1) to give compound 8-13. LCMS: MSm/z=938.2[M+H]⁺.

Step 13: Synthesis of Compound 8-14

Compound 8-13 (0.15 g, 159.91 μmol, 1 eq) was added to anhydrousdichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. Themixture was reacted at 25° C. for 2.5 hr. The reaction solution wasadded to 10 mL of saturated sodium bicarbonate solution, and extractedwith 5 mL×2 of dichloromethane. The organic phases were combined, driedwith anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated to give compound 8-14. LCMS: MS m/z=698.2[M+H]⁺.

Step 14: Synthesis of Compound 8-15

Compound 8-14 (0.17 g, 243.65 μmol, 1 eq) was added to anhydrousmethanol (2 mL) and anhydrous tetrahydrofuran (2 mL). Palladium oncarbon (0.15 g, 10% mass content) was added and the mixture was reactedat 25° C. under hydrogen (15 psi) for 0.5 hr. The reaction solution wasdirectly filtered to recover the catalyst and the filtrate wasconcentrated to give compound 8-15 as a yellow solid. LCMS: MSm/z=564.2[M+H]⁺.

Step 15: Synthesis of Compounds 8A and 8B

Compound 8-15 (60 mg, 106.46 μmol, 1 eq), 2-fluoroacrylic acid (11.50mg, 127.75 μmol, 1.2 eq) and2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(60.72 mg, 159.69 μmol, 1.5 eq) were added to N,N-dimethylformamide (1mL). N,N-diisopropylethylamine (41.28 mg, 319.38 μmol, 55.63 μL, 3 eq)was added, and the mixture was reacted at 25° C. for 0.5 hr. Thereaction solution was added to 10 mL of saturated ammonium chloride, andextracted with 5 mL×2 of ethyl acetate. The organic phases werecombined, washed with 5 mL×2 of saturated brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated to givecompound 8-16, which was purified by a high-performance liquidchromatography column (column: Phenomenex Gemini-NX 150*30 mm*5 μm;mobile phase: [H₂O(0.1% TFA)-ACN]; acetonitrile %: 20%-50%, 9 min). Thefractions were concentrated under vacuum. 5 mL of deionized water and0.5 mL of acetonitrile were added, and then 2 drops of 1M hydrochloricacid solution were added. The mixture was concentrated under vacuum togive compound 8A hydrochloride ((time-to-peak: 1.379 min). SFCresolution method (column: Chiralcel OD-3, 50×4.6 mm I.D., 3 μm; Mobilephase: A (CO2) and B (methanol, containing 0.05% diisopropylamine);Gradient: B %=5-50%, 3 min; Flow rate: 3.4 mL/min; Wavelength: 220 nm;Pressure: 1800 psi. Optical purity: 80.82%. LCMS: MS m/z=636.4[M+H]⁺)and compound 8B hydrochloride ((time-to-peak: 1.789 min). SFC resolutionmethod (column: Chiralcel OD-3, 50×4.6 mm I.D., 3 μm; Mobile phase: A(CO2) and B (methanol, containing 0.05% diisopropylamine); Gradient: B%=5-50%, 3 min; Flow rate: 3.4 mL/min; Wavelength: 220 nm; Pressure:1800 psi. Optical purity: 75.56%). ¹H NMR (400 MHz, CDCl₃) δ=6.59 (d,J=8.4 Hz, 1H), 5.50-5.33 (m, 1H), 5.29-5.16 (m, 2H), 4.82-4.69 (m, 2H),4.39 (dd, J=5.2, 10.8 Hz, 1H), 4.16 (dd, J=6.8, 10.4 Hz, 1H), 4.04 (s,2H), 3.94 (d, J=14.0 Hz, 1H), 3.68 (d, J=11.6 Hz, 1H), 3.50-3.32 (m,2H), 3.10 (br t, J=7.2 Hz, 1H), 3.05-2.94 (m, 2H), 2.79 (br d, J=7.2 Hz,2H), 2.71-2.62 (m, 1H), 2.48 (s, 3H), 2.39 (q, J=4.0 Hz, 3H), 2.32-2.22(m, 1H), 2.11-1.99 (m, 1H), 1.93-1.66 (m, 6H). LCMS: MS m/z=636.4[M+H]⁺.

Example 9

Step 1: Synthesis of Compound 9-3A

Anhydrous tetrahydrofuran (30 mL) was added to a dry reaction flask, andthen compound 9-6 (1.5 g, 6.07 mmol, 1 eq) was added. The reactionsystem was cooled down to 10° C. Lithium aluminum hydride (690.66 mg,18.20 mmol, 3 eq) was added in batches, and the reaction system wasreacted at 15° C. for 16 h. Sodium sulfate decahydrate (4 g) was addedto the reaction solution and the mixture was stirred for 1 h. Themixture was filtered. The filter cake was added to tetrahydrofuran (20mL×2) and the mixture was stirred for 0.5 hr. The mixtures wereseparately filtered. The filtrates were combined, and concentrated underreduced pressure to give compound 9-3A, which was used directly in thenext step without purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 5.25-4.98(m, 1H) 3.75-3.65 (m, 1H) 3.61-3.43 (m, 2H) 2.83-2.74 (m, 1H) 2.71-2.56(m, 1H) 2.39 (s, 3H) 2.14-2.03 (m, 2H). LCMS m/z=134.2 [M+H]⁺.

Step 2: Synthesis of Compound 9-2

N,N-dimethylformamide (6 mL) was added to a dry reaction flask, followedby compound 8-10 (0.55 g, 722.04 μmol, 1 eq), N,N-diisopropylethylamine(279.95 mg, 2.17 mmol, 377.29 uL, 3 eq) and compound 9-1A (289.22 mg,1.44 mmol, 2 eq). The reaction system was reacted at 50° C. undernitrogen for 50 min. Additional compound 9-1A (50 mg) was added, and themixture was reacted for another 0.5 h. TLC (petroleum ether:ethylacetate=3:1) showed that the raw material disappeared and new spotsappeared. After the reaction system was cooled down to room temperature(15° C.), the reaction solution was added to saturated ammonium chloridesolution (30 mL), and extracted with methyl tert-butyl ether (10 mL×2).The organic phases were combined, washed with saturated brine (20 mL×2),dried with anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to give compound 9-2, which was useddirectly in the next step without purification. LCMS m/z=812.4[M+H]⁺

Step 3: Synthesis of Compound 9-3

Dichloromethane (10 mL) was added to a dry reaction flask, and thencompound 9-2 (0.65 g, 800.57 μmol, 1 eq) and m-chloroperoxybenzoic acid(207.23 mg, 960.68 μmol, 80% purity, 1.2 eq) were added. The reactionsystem was reacted at 15° C. for 0.5 hr. The reaction solution waspoured into water (20 mL). Sodium thiosulfate solution (20 mL, 10%) wasadded and the mixture showed negative by starch-KI paper. The mixturewas then extracted with dichloromethane (20 mL). The organic phase wasdried with anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure at 40° C. to give a crude product,which was purified by column (petroleum ether:ethyl acetate=3:1 to 0:1)according to TLC (petroleum ether:ethyl acetate=0:1, RF=0.53) to givecompound 9-3. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.16 (d, J=7.60 Hz, 4H) 6.84(d, J=8.40 Hz, 4H) 6.66 (s, 1H) 5.26 (d, J=10.42 Hz, 1H), 4.85-4.68 (m,2H) 4.39-4.20 (m, 4H) 4.09-3.90 (m, 2H) 3.89-3.67 (m, 7H) 3.66-3.42 (m,2H) 3.40-3.16 (m, 2H) 3.14-2.75 (m, 4H) 2.34 (d, J=4.00 Hz, 3H) 1.49 (s,9H) 1.43-1.37 (m, 2H) 1.19 (m, 2H), LCMS m/z=828.2[M+H]⁺

Step 4: Synthesis of Compound 9-4

Toluene (6 mL) was added to a dry reaction flask, and then compound 9-3A(289.51 mg, 2.17 mmol, 28.68 μL, 4 eq) was added. The reaction systemwas cooled down to 0° C. Sodium tert-butoxide (208.93 mg, 2.17 mmol, 4eq) was added and the reaction system was reacted at 0 to 5° C. for 10min. A solution of compound 9-3 (0.45 g, 543.53 μmol, 1 eq) in toluene(2 mL) was added and the reaction system was reacted at 0 to 5° C. for0.5 hours. The reaction solution was washed with saturated ammoniumchloride (20 mL×2), followed by saturated brine (20 mL), dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give compound 9-4, which was used directly inthe next step without purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.15(d, J=7.60 Hz, 4H) 6.84 (d, J=8.40 Hz, 4H) 6.62 (d, J=7.20 Hz, 1H)5.29-5.04 (m, 3H) 4.29 (d, J=14.80 Hz, 4H) 3.80 (s, 6H) 3.44-3.34 (m,2H) 3.30-3.21 (m, 1H) 3.06-2.79 (m, 2H) 2.68-2.52 (m, 5H) 2.47 (s, 3H)2.42-2.27 (m, 5H) 2.25-2.08 (m, 5H) 1.49 (s, 9H) 1.38 (d, J=6.40 Hz, 2H)1.14 (d, J=6.80 Hz, 1H). LCMS m/z=897.3 [M+H]⁺

Step 5: Synthesis of Compound 9-5

Dichloromethane (15 mL) was added to a dry reaction flask, and thencompound 9-4 (0.6 g, 668.91 μmol, 1 eq) and trifluoroacetic acid (3 mL)were added. The reaction system was reacted at 15° C. for 2.5 h.Additional trifluoroacetic acid (0.5 mL) was added, and the mixture wasreacted for another 1 h. Additional trifluoroacetic acid (0.5 mL) wasadded, and the mixture was reacted for another 1 h. The reactionsolution was slowly added to saturated sodium bicarbonate solution (80mL), and extracted with dichloromethane (30 mL×2). The organic phaseswere combined, dried with anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure to give a crudeproduct, which was purified by column(dichloromethane:methanol=100:0-1:1) according to TLC(dichloromethane:methanol=5:1) to give compound 9-5. ¹H NMR (400 MHz,CDCl₃) δ ppm 6.59 (d, J=8.40 Hz, 1H) 5.29-5.07 (m, 2H) 4.75-4.67 (m, 1H)4.52-4.38 (m, 1H) 4.32-4.16 (m, 1H) 4.08-3.87 (m, 3H) 3.66-3.26 (m, 4H)3.25-2.8 (m, 6H) 2.72-2.59 (m, 1H) 2.54 (d, J=2.00 Hz, 3H) 2.44-2.26 (m,3H) 2.11-1.86 (m, 1H) 1.52 (d, J=6.80 Hz, 1H) 1.26 (d, J=6.80 Hz, 2H).LCMS m/z=557.3[M+H]⁺.

Step 6: Synthesis of Compounds 9A and 9B

Dichloromethane (5 mL) was added to a dry reaction flask, followed byacrylic acid (21.75 mg, 301.85 μmol, 20.72 μL, 1.2 eq) andN,N-diisopropylethylamine (97.53 mg, 754.62 μmol, 131.44 μL, 3 eq). Thereaction system was cooled down to −60° C. and0-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (114.77 mg, 301.85 μmol, 1.2 eq) was added. Thereaction system was reacted at −60° C. for 10 min. Compound 9-5 (0.14 g,251.54 μmol, 1 eq) was added, and the mixture was reacted for another 1hour. The reaction solution was diluted with dichloromethane (10 mL),washed with saturated ammonium chloride solution (10 mL×2), dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure. The product was purified by a high-performanceliquid chromatography column {(column: Phenomenex luna C18 80*40 mm*3μm; mobile phase: [H₂O(0.04% HCl)-ACN]; acetonitrile %: 20%-32%, 7min]}, lyophilized, and then subjected to chiral separation according toSFC {(column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase:[0.1%₀NH₃H₂O MEOH]; MeOH %: 60%-60%, 9 min)} to give compound 9A((time-to-peak in chiral column: 1.594 min), SFC analysis method(column: Chiralcel OD-3, 50×4.6 mm I.D., 3 μm; Mobile phase: A (CO2) andB (methanol, containing 0.05% diisopropylamine); Gradient: B %=5-50%, 3min; Flow rate: 3.4 mL/min; Wavelength: 220 nm; Pressure: 1800 psi.Optical purity: 100%). ¹H NMR (400 MHz, CDCl₃) δ ppm 6.71-6.49 (m, 2H)6.42-6.28 (m, 1H) 5.77 (d, J=10.80 Hz, 1H) 5.50 to 5.04 (m, 3H) 4.71 (s,3H) 4.49-4.22 (m, 2H) 4.03 (s, 3H) 3.78 (d, J=9.20 Hz, 1H) 3.64 (s, 1H)3.51-3.17 (m, 4H) 3.14-3.00 (m, 4H) 2.64-2.48 (m, 1H) 2.40 (d, J=4.00Hz, 4H) 1.16 (d, J=10.40 Hz, 3H). LCMS m/z=611.3 [M+H]⁺) and compound 9B((time-to-peak in chiral column: 1.903 min), SFC analysis method(column: Chiralcel OD-3, 50×4.6 mm I.D., 3 μm; Mobile phase: A (CO2) andB (methanol, containing 0.05% diisopropylamine); Gradient: B %=5-50%, 3min; Flow rate: 3.4 mL/min; Wavelength: 220 nm; Pressure: 1800 psi.Optical purity: 100%). ¹H NMR (400 MHz, CDCl₃) δ ppm 6.69-6.54 (m, 2H)6.42-6.30 (m, 1H) 5.77 (d, J=10.80 Hz, 1H) 5.47-5.01 (m, 3H) 4.71 (s,3H) 4.49-4.23 (m, 2H) 4.03 (s, 3H) 3.94-3.72 (m, 1H) 3.64 (s, 1H)3.53-3.22 (m, 4H) 3.14-3.01 (m, 4H) 2.62-2.49 (m, 1H) 2.40 (d, J=4.00Hz, 4H) 1.16 (d, J=10.40 Hz, 3H). LCMS m/z=611.3 [M+H]⁺).

Example 10

Step 1: Synthesis of Compounds 10-1A and 10-1B

Compound 8-9 (9 g, 15.27 mmol, 1 eq) was dissolved in ethanol (100 mL)and water (20 mL), and then 2-methyl-2-thioisourea sulfate (42.49 g,152.65 mmol, 10 eq) and sodium bicarbonate (25.65 g, 305.31 mmol, 11.87mL, 20 eq) were added. The reaction solution was stirred at 30° C. for 4hr. 100 mL of saturated ammonium chloride solution was added to thereaction solution. The mixture was extracted with ethyl acetate (100mL×2), washed with 80 mL of saturated brine, dried with anhydrous sodiumsulfate, and filtered. The filtrate was concentrated to give a crudeproduct, which was purified by column (petroleum ether:ethylacetate=10%-20%-30%) according to TLC (petroleum ether:ethylacetate=0:1), and then resolved by SFC (Column: DAICEL CHIRALPAK AD (250mm*50 mm, 10 μm); mobile phase: [0.1% NH₃.H₂O EtOH]; EtOH %: 45%-45%,6.3 min) to give compound 10-1A (time-to-peak: 1.665) and Compound 10-1B(time-to-peak: 2.446).

Step 2: Synthesis of Compound 10-2

Compound 10-1A (2 g, 3.18 mmol, 1 eq) was dissolved in dichloromethane(20 mL), and N,N-diisopropylethylamine (1.23 g, 9.53 mmol, 1.66 mL, 3eq) was added. The reaction system was cooled down to 0 to 10° C., andtriflic anhydride (1.34 g, 4.76 mmol, 786.11 μL, 1.5 eq) was slowlyadded. The reaction system was reacted at this temperature for 15 min.Saturated aqueous ammonium chloride solution (15 mL) was poured into thereaction system and the layers were separated. The aqueous phase wasextracted with dichloromethane (15 mL×2). The organic phases werecombined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated to give a crude product. The crude product waspurified by column chromatography (PE/EtOAc=100/1-0/1) according to TLC(PE/EtOAc=10/1) to give compound 10-2. LCMS m/z=762.2[M+H]⁺.

Step 3: Synthesis of Compound 10-3

N,N-dimethylformamide (2 mL) was added to a dry reaction flask, followedby compound 10-2 (0.16 g, 210.05 μmol, 1 eq), N,N-diisopropylethylamine(81.44 mg, 630.15 μmol, 109.76 μL, 3 eq) and compound 10-2A (50.48 mg,252.06 μmol, 1.2 eq). The reaction system was reacted at 50° C. undernitrogen for 1 hour. TLC (petroleum ether:ethyl acetate=3:1) showed thatthe raw material disappeared and new spots appeared. Methyl tert-butylether (10 mL) was added to the reaction solution. The mixture was washedwith saturated ammonium chloride solution (20 mL×2) followed bysaturated brine (10 mL), dried with anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to givecompound 10-3, which was used directly in the next step withoutpurification. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.12 (d, J=8.80 Hz, 4H) 6.81(d, J=8.80 Hz, 4H) 6.60 (d, J=8.80 Hz, 1H) 5.19 (d, J=8.00 Hz, 1H) 4.72(s, 2H) 4.37-4.22 (m, 4H) 3.88 (d, J=13.2 Hz, 1H) 3.77 (s, 6H) 3.71-3.56(dd, J=12.80, 13.20 Hz, 2H) 3.40 (dd, J=12.40, 12.40 Hz, 1H) 3.31 (m,2H) 3.20 (s, 1H) 3.03-2.91 (m, 2H) 2.50 (s, 3H) 2.35-2.25 (m, 3H) 1.46(s, 9H) 1.13 (d, J=6.80 Hz, 3H).

Step 4: Synthesis of Compound 10-4

Dichloromethane (5 mL) was added to a dry reaction flask and compound10-3 (0.21 g, 258.64 μmol, 1 eq) and m-chloroperoxybenzoic acid (66.95mg, 310.37 μmol, 80% purity, 1.2 eq) were added. The reaction system wasreacted at 15° C. for 0.5 h. To the reaction solution was added sodiumthiosulfate solution (15 mL, 10%). The mixture showed negative bystarch-KI paper. The mixture was then extracted with dichloromethane (15mL), dried with anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to give a crude product, which waspurified by column (petroleum ether:ethyl acetate=10:1 to 0:1) accordingto TLC (petroleum ether:ethyl acetate=0:1) to give compounds 10-4 and10-4A. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.20 (s, 4H), 6.84 (d, J=8.80 Hz,4H), 6.79-6.62 (s, 1H), 5.24 (d, J=10.80 Hz, 1H), 4.87-4.74 (m, 2H),4.36 (s, 4H), 3.99-3.83 (m, 3H), 3.83-3.71 (m, 7H), 3.62-3.43 (m, 2H),3.40-3.27 (m, 3H), 3.22-3.06 (m, 2H), 2.92 (d, J=5.20 Hz, 1H), 2.34 (s,3H), 1.49 (s, 9H), 1.16 (d, J=6.80 Hz, 3H). LCMS m/z=828.2M+H]⁺.

Step 3: Synthesis of Compound 10-5

Toluene (1 mL) was added to a dry reaction flask and compound 1-11A(38.95 mg, 338.19 μmol, 4 eq) was added. The reaction system was cooleddown to 0° C. Sodium tert-butoxide (32.50 mg, 338.19 μmol, 4 eq) wasadded and the mixture was reacted for 10 min. A mixture of compound 10-4(0.07 g, 84.55 μmol, 1 eq) and 10-4A (71.35 mg, 84.55 μmol, 1 eq) intoluene (1 mL) was added and the mixture was reacted for 0.5 h. To thereaction solution was added 10 mL of ethyl acetate and then the mixturewas washed with 10 mL of saturated ammonium chloride solution andsaturated brine, respectively. The organic phase was dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give compound 10-5, which was used directly inthe next step without purification. LCMS m/z=879.3 [M+H]⁺.

Step 4: Synthesis of Compound 10-6

Dichloromethane (5 mL) was added to a dry reaction flask, and compound10-5 (0.16 g, 182.03 μmol, 1 eq) and trifluoroacetic acid (1.25 mL) wereadded. The reaction system was stirred at 18° C. for 1.5 hours.Additional trifluoroacetic acid (0.25 mL) was added and the mixture wasreacted for another 1.5 h. Water (5 mL) was added to the reactionsolution. The aqueous phase was collected, adjusted to pH of 8 withsaturated sodium bicarbonate solution, and extracted withdichloromethane (20 mL×2). The organic phases were combined, dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give compound 10-6, which was used directly inthe next step without purification. LCMS m/z=539.2[M+H]⁺.

Step 5: Synthesis of Compound 10

Dichloromethane (5 mL) was added to a dry reaction flask, followed byacrylic acid (5.54 mg, 76.87 μmol, 5.28 μL, 2 eq), compound 10-6 (23 mg,38.43 μmol, 90% purity, 1 eq) and N,N-diisopropylethylamine (14.90 mg,115.30 μmol, 20.08 μL, 3 eq). The reaction system was cooled down to−60° C. and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (17.54 mg, 46.12 μmol, 1.2 eq) was added. Themixture was then stirred for 0.5 hr. The reaction mixture was combinedwith the batch of compound 10-6 (19.49 mg) for treatment. Water (5 ml)was added to the reaction solution, and the layers were separated. Theorganic phase was concentrated under reduced pressure and separated on ahigh-performance liquid chromatography column {column: Phenomenex lunaC18 80*40 mm*3 μm; [H₂O(0.04% HCl)-ACN]; acetonitrile %: 20%-40%, 7 min}to give compound 10. LCMS m/z=593.4[M+H]⁺.

Example 11

Step 1: Synthesis of Compound 11-2

N,N-dimethylformamide (2 mL) was added to a dry reaction flask, followedby compound 10-2 (0.16 g, 210.05 μmol, 1 eq), N,N-diisopropylethylamine(81.44 mg, 630.15 μmol, 109.76 μL, 3 eq) and compound 11-1 (54.02 mg,252.06 μmol, 1.2 eq). The reaction system was reacted at 50° C. undernitrogen for 1 h. The mixture was combined with the batch of compound10-2 (50 mg) for treatment. Methyl tert-butyl ether (10 mL) was added tothe reaction solution. The mixture was washed with saturated ammoniumchloride solution (10 mL×2), followed by saturated brine (10 mL), driedwith anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to give compound 11-2, which wasused directly in the next step without purification. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.14 (d, J=8.80 Hz, 4H), 6.84 (d, J=8.40 Hz, 4H), 6.62 (d,J=8.80 Hz, 1H), 5.19 (br d, J=8.00 Hz, 1H), 4.76 (s, 2H), 4.37-4.22 (m,5H), 3.80 (s, 7H), 3.58-3.35 (m, 3H), 3.22 (s, 2H), 3.04-2.93 (m, 1H),2.52 (s, 3H), 2.38-2.30 (m, 3H), 1.49 (s, 9H), 1.34 (dd, J=6.80, 6.40Hz, 6H).

Step 2: Synthesis of Compound 11-3

Dichloromethane (5 mL) was added to a dry reaction flask, and compound11-2 (0.20 g, 242.14 μmol, 1 eq) and m-chloroperoxybenzoic acid (62.68mg, 290.57 μmol, 80% purity, 1.2 eq) were added. The reaction system wasreacted at 15° C. for 0.5 h. The mixture was combined with the batch ofcompound 11-2 (50 mg) for treatment. Sodium thiosulfate solution (15 mL,10%) was added to the reaction solution and the mixture showed negativeby starch-KI paper. The mixture was extracted with dichloromethane (10mL), dried with anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to give a crude product, which waspurified by column (petroleum ether:ethyl acetate=10:1 to 0:1) accordingto TLC (petroleum ether:ethyl acetate=0:1) to give a mixture of compound11-3 and compound 11-3A. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.17 (d, J=6.40Hz, 4H) 6.84 (d, J=8.40 Hz, 4H) 6.67 (s, 1H) 5.23 (d, J=11.20 Hz, 1H)4.90-4.74 (m, 2H) 4.32 (d, J=12.00 Hz, 4H) 3.84-3.75 (m, 9H) 3.68-3.39(m, 3H) 3.31-3.10 (m, 3H) 2.89 (d, J=10.40 Hz, 2H) 2.34 (d, J=3.60 Hz,3H) 1.49 (s, 9H) 1.42-1.29 (m, 6H). LCMS m/z=842.2[M+H]⁺.

Step 3: Synthesis of Compound 11-4

Toluene (1 mL) was added to a dry reaction flask and compound 1-11A(46.51 mg, 403.82 μmol, 4 eq) was added. The reaction system was cooleddown to 0° C. Sodium tert-butoxide (38.81 mg, 403.82 μmol, 4 eq) wasadded and the mixture was reacted for 10 min. A mixture of compound 11-3(0.085 g, 100.96 μmol, 1 eq) and compound 11-3A (86.62 mg, 100.96 μmol,1 eq) in toluene (1 mL) was added and the reaction system was stirredfor 0.5 h. The mixture was combined with the batch of compound 11-3 (10mg) for treatment. To the reaction solution was added 10 mL of ethylacetate, and then the mixture was washed with 10 mL of saturatedammonium chloride solution and saturated brine, respectively, dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give compound 11-4, which was used directly inthe next step without purification. LCMS m/z=893.4[M+H]⁺.

Step 4: Synthesis of Compound 11-5

Dichloromethane (5 mL) was added to a dry reaction flask, and compound11-4 (0.13 g, 145.57 μmol, 1 eq) and trifluoroacetic acid (1.25 mL) wereadded. The reaction system was reacted at 18° C. for 1.5 h. Additionaltrifluoroacetic acid (0.25 mL) was added and the mixture was reacted foranother 1.5 h. The mixture was combined with the batch of 11-4 (15 mg)for treatment. Water (5 mL) was added to the reaction solution. Theaqueous phase was collected, adjusted to pH of 8 with saturated sodiumbicarbonate solution, and extracted with dichloromethane (20 mL×2). Theorganic phases were combined, dried with anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure to givecompound 11-5, which was used directly in the next step withoutpurification. LCMS m/z=553.2[M+H]⁺.

Step 5: Synthesis of Compound 11

Dichloromethane (5 mL) was added to a dry reaction flask, and acrylicacid (14.08 mg, 195.44 μmol, 13.41 μL, 2 eq), compound 11-5 (60.00 mg,97.72 μmol, 90% purity, 1 eq) and N,N-diisopropylethylamine (37.89 mg,293.16 μmol, 51.06 μL, 3 eq) were then added. The reaction system wascooled down to −60° C.O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (44.59 mg, 117.26 μmol, 1.2 eq) was added. Themixture was then stirred for 0.5 h. The reaction mixture was combinedwith the batch of compound 11-5 (20 mg) for treatment. Water (5 ml) wasadded to the reaction solution. The layers were separated. The organicphase was concentrated under reduced pressure and purified by ahigh-performance liquid chromatography column {column: Phenomenex lunaC18 80*40 mm*3 μm; mobile phase: [H₂O(0.04% HCl)-ACN]; acetonitrile %:15%-40%, 7 min} to give compound 11. ¹H NMR (400 MHz, CD₃OD) δ=6.92-6.75(m, 1H), 6.74-6.70 (m, 1H), 6.33-6.24 (m, 1H), 5.88-5.77 (m, 1H),5.28-5.18 (m, 1H), 4.82-4.63 (m, 2H), 4.56-4.43 (m, 1H), 4.42-4.23 (m,1H), 4.01-3.81 (m, 2H), 3.79-3.59 (m, 2H), 3.57-3.41 (m, 1H), 3.32-3.20(m, 5H), 3.17-3.02 (m, 3H), 2.84 (m, 2H), 2.51-2.35 (m, 3H), 2.31-1.99(m, 3H), 1.49-1.29 (m, 6H). LCMS m/z=607.5[M+H]⁺.

Example 12

Step 1: Synthesis of Compound 12-2

N,N-dimethylformamide (2 mL) was added to a dry reaction flask, followedby compound 10-2 (0.2 g, 262.56 μmol, 1 eq), N,N-diisopropylethylamine(101.80 mg, 787.69 μmol, 137.20 μL, 3 eq) and compound 9-1A (63.10 mg,315.07 μmol, 1.2 eq). The reaction system was reacted at 50° C. undernitrogen for 30 min. Additional compound 9-1A (30 mg, 0.6 eq) was addedand the mixture was reacted for another 30 min. To the reaction solutionwas added saturated ammonium chloride solution (10 mL), and the mixturewas extracted with methyl tert-butyl ether (5 mL). The organic phasesolution was washed successively with saturated ammonium chloridesolution (10 mL) and saturated brine (10 mL), dried with anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure to give compound 12-2, which was used directly in thenext step without purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.14 (d,J=8.80 Hz, 4H) 6.84 (d, J=8.40 Hz, 4H) 6.62 (d, J=8.80 Hz, 1H) 5.21 (d,J=7.20 Hz, 1H) 4.78-4.63 (m, 2H) 4.38-4.15 (m, 4H) 4.00-3.82 (m, 2H)3.80 (s, 6H) 3.73-3.60 (m, 1H) 3.48-3.33 (m, 1H) 3.22 (s, 2H) 3.16-2.80(m, 3H) 2.51 (s, 3H) 2.38-2.30 (m, 3H) 1.49 (s, 9H) 1.38 (d, J=6.80 Hz,3H). LCMS m/z=812.3 [M+H]⁺.

Step 2: Synthesis of Compound 12-3

Dichloromethane (5 mL) was added to a dry reaction flask, followed bycompound 12-2 (0.18 g, 221.70 μmol, 1 eq) and m-chloroperoxybenzoic acid(57.39 mg, 266.03 μmol, 80% purity, 1.2 eq). The reaction system wasreacted at 15° C. for 0.5 h. The mixture was combined with the batch ofcompound 12-2 (30 mg) for treatment. Sodium thiosulfate solution (10 mL,10%) was added to the reaction solution, and the mixture showed negativeby starch-KI paper. The mixture was extracted with dichloromethane (3mL), dried with anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to give a crude product, which waspurified by column (petroleum ether:ethyl acetate=10:1 to 0:1) accordingto TLC (petroleum ether:ethyl acetate=0:1) to give compound 12-3. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.17 (br s, 4H) 6.84 (br d, J=8.40 Hz, 4H) 6.67(br s, 1H) 5.25 (br d, J=9.60 Hz, 1H) 4.89-4.64 (m, 2H) 4.32 (br d,J=10.40 Hz, 4H) 4.09-3.86 (m, 3H) 3.84-3.68 (m, 7H) 3.64-3.51 (m, 1H)3.37-2.97 (m, 4H) 2.95-2.81 (m, 3H) 2.34 (br d, J=3.60 Hz, 3H) 1.49 (s,9H) 1.41 (br s, 3H). LCMS m/z=828.2[M+H]⁺.

Step 3: Synthesis of Compound 12-4

Toluene (1 mL) was added to a dry reaction flask, then compound 12-3A(66.52 mg, 471.06 μmol, 3 eq) was added. The reaction system was cooleddown to 0° C., then tert-butanol sodium (45.27 mg, 471.06 μmol, 3 eq)was added. The mixture was stirred for 10 min, and then a solution ofcompound 12-3 (0.13 g, 157.02 μmol, 1 eq) in toluene (0.5 mL) was added.The mixture was stirred for 0.5 h. The mixture was combined with thebatch of compound 12-3 (20 mg) for treatment. 10 mL of ethyl acetate wasadded to the reaction solution. The mixture was then washed with 10 mLof saturated ammonium chloride solution and saturated brine,respectively, dried with anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure to give compound 12-4,which was used directly in the next step without purification. LCMSm/z=905.3 [M+H]⁺.

Step 4: Synthesis of Compound 12-5

Dichloromethane (6 mL) was added to a dry reaction flask, and thencompound 12-4 (0.18 g, 198.89 μmol, 1 eq) and trifluoroacetic acid (1.5mL) were added. The reaction system was stirred at 18° C. for 3.5 hours.Water (5 mL) was added to the reaction solution. The aqueous phase wascollected, adjusted to pH of 8 with saturated sodium bicarbonatesolution, and extracted with dichloromethane (20 mL×2). The organicphases were combined, dried with anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure to give compound12-5, which was used directly in the next step without purification.LCMS m/z=565.2[M+H]⁺.

Step 5: Synthesis of Compound 12

Dichloromethane (5 mL) was added to a dry reaction flask and stirred.Acrylic acid (11.49 mg, 159.40 μmol, 10.94 μL, 2 eq), compound 12-5 (50mg, 79.70 μmol, 90% purity, 1 eq) and N,N-diisopropylethylamine (30.90mg, 239.10 μmol, 41.65 μL, 3 eq) were added. The reaction system wascooled down to −60° C. andO-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (36.37 mg, 95.64 μmol, 1.2 eq) was added. Themixture was then stirred for 0.5 h. The reaction mixture was combinedwith the batch of compound 12-5 (20 mg) for treatment. To the reactionsolution was added water (5 ml). The layers were separated. The organicphase was dried with anhydrous sodium sulfate and filtered. The filtratewas concentrated under reduced pressure to give a crude product, whichwas purified by a high-performance liquid chromatography column {column:Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [H₂O(0.04% HCl)-ACN];acetonitrile %: 15%-40%, 7 min} to give compound 12 (time-to-peak:1.509). SFC analysis method (column: Chiralcel OD-3, 50×4.6 mm I.D., 3μm; Mobile phase: A (CO2) and B (methanol, containing 0.05%diisopropylamine); Gradient: B %=5-50%, 3 min; Flow rate: 3.4 m/min;Wavelength: 220 nm; Pressure: 1800 psi. Optical purity: 99.4%. ¹H NMR(400 MHz, CD₃OD) δ=6.89-6.71 (m, 1H), 6.71-6.65 (d, J=8.8 Hz, 1H),6.32-6.19 (m, 1H), 5.84-5.75 (m, 1H), 5.26-5.15 (m, 1H), 4.68-4.60 (m,1H), 4.52 (s, 2H), 4.50-4.45 (m, 1H), 4.39-4.32 (m, 1H), 4.27-4.16 (m,1H), 4.15-3.89 (m, 2H), 3.76-3.61 (m, 2H), 3.60-3.32 (m, 2H), 3.28-3.13(m, 3H), 3.09-3.00 (m, 1H), 2.96-2.85 (m, 1H), 2.38-2.32 (m, 3H),2.32-2.24 (m, 2H), 2.24-2.12 (m, 4H), 2.12-2.03 (m, 2H), 1.42-1.31 (m,3H). LCMS m/z=619.3[M+H]⁺.

Example 13

Step 1: Synthesis of Compound 13-2

N,N-dimethylformamide (4 mL) was added to a dry reaction flask, followedby compound 10-2 (220 mg, 288.82 μmol, 1 eq) and compound 13-1 (115.69mg, 577.64 μmol, 2 eq). The mixture was stirred, and thenN,N-diisopropylethylamine (111.98 mg, 866.45 μmol, 150.92 μL, 3 eq) wasadded. The reaction system was heated to 50° C. and stirred for 1 hr.The reaction solution was extracted with ethyl acetate (30 mL), washedonce with saturated ammonium chloride (15 mL) and once with saturatedbrine (15 mL), dried with anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure to give a crude productof compound 13-2, which was used directly in the next step withoutpurification. LCMS m/z=812.2[M+H]⁺.

Step 2: Synthesis of Compound 13-3

Dichloromethane (10 mL) was added to a dry reaction flask and compound13-2 (200.00 mg, 246.33 μmol, 1 eq) was added. The mixture was stirred,and m-chloroperoxybenzoic acid (60.01 mg, 295.59 μmol, 85% purity, 1.2eq) was added. The reaction system was stirred at 25° C. for 1 h. Thereaction solution was diluted with dichloromethane (20 mL), then washedonce with 5% sodium thiosulfate (10 mL) and once with saturated brine(10 mL), dried with anhydrous sodium sulfate and filtered. The filtratewas concentrated under reduced pressure to give a crude product, whichwas purified by column (petroleum ether:ethyl acetate=90:10 to 50:50)according to TLC (petroleum ether:ethyl acetate=1:1) to give compound13-3. LCMS m/z=828.3[M+H]⁺.

Step 3: Synthesis of Compound 13-4

Toluene (5 mL) was added to a dry reaction flask, and then compound1-11A (112.68 mg, 978.35 μmol, 4.5 eq) was added. The mixture wasstirred. Then sodium tert-butoxide (94.02 mg, 978.35 μmol, 4.5 eq) wasadded and the reaction system was cooled down to 0° C. and stirred for10 min. Compound 13-3 (180 mg, 217.41 μmol, 1 eq) was then added and thereaction system was stirred at 0° C. for 1 hour. The reaction mixturewas combined with the batch of compound 13-3 (60 mg) for treatment. Thereaction solution was extracted with ethyl acetate (30 mL). The organicphase solution was washed once with saturated ammonium chloride solution(10 mL) and once with saturated brine (10 mL), dried with anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure to give a crude product of compound 13-4, which was useddirectly in the next step without purification. LCMS m/z=879.3 [M+H]⁺.

Step 4: Synthesis of Compound 13-5

Dichloromethane (5 mL) was added to a dry reaction flask, and thencompound 13-4 (260 mg, 295.79 μmol, 1 eq) was added. The mixture wasstirred. Potassium acetate (2.82 g, 24.70 mmol, 1.83 mL, 83.50 eq) wasadded and the reaction system was stirred at 20° C. for 2 hr. Water (30mL) was added to the reaction solution and the layers were separated.The aqueous phase was adjusted to pH of 9 with saturated sodiumbicarbonate, and then extracted with ethyl acetate (15 mL×2). Theorganic phases were combined, washed with saturated brine (10 mL), driedwith anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure to give a crude product of compound13-5, which was directly used in the next step without purification.LCMS m/z=539.2[M+H]⁺.

Step 5: Synthesis of Compound 13

Dichloromethane (5 mL) was added to a dry reaction flask, followed byacrylic acid (10.84 mg, 150.40 μmol, 10.32 μL, 1 eq), compound 13-5 (90mg, 150.40 μmol, 90% purity, 1 eq) and N,N-diisopropylethylamine (58.31mg, 451.19 μmol, 78.59 μL, 3 eq). The mixture was stirred. The reactionsystem was cooled down to −60° C., andO-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (68.62 mg, 180.47 μmol, 1.2 eq) was added. Themixture was stirred for 0.5 h. The reaction mixture was combined withthe batch of compound 13-5 (30 mg) for treatment. Water (5 mL) was addedto the reaction solution, and the layers were separated. The organicphase solution was directly concentrated under reduced pressure to givea crude product, which was purified by a high-performance liquidchromatography column {column: Welch Xtimate C18 100*25 mm*3 μm; mobilephase: [H₂O(0.05% HCl)-ACN]; acetonitrile %: 15%-45%, 8 min} to givecompound 13 (time-to-peak: 1.683). SFC analysis method (column:Chiralcel OD-3, 50×4.6 mm I.D., 3 μm; Mobile phase: A (CO2) and B(methanol, containing 0.05% diisopropylamine); Gradient: B %=5-50%, 3min; Flow rate: 3.4 mL/min; Wavelength: 220 nm; Pressure: 1800 psi,Optical purity: 95.48%). ¹H NMR (400 MHz, CD₃OD) δ=6.87-6.73 (m, 1H),6.68 (d, J=8.4 Hz, 1H), 6.25 (dd, J=3.8, 16.6 Hz, 1H), 5.78 (d, J=11.6Hz, 1H), 5.20 (dd, J=4.0, 11.2 Hz, 1H), 4.83-4.75 (m, 2H), 4.74-4.61 (m,2H), 4.60-4.45 (m, 2H), 4.32 (d, J=13.0 Hz, 1H), 4.17-3.92 (m, 1H),3.90-3.80 (m, 1H), 3.71-3.57 (m, 2H), 3.55-3.42 (m, 1H), 3.39-3.32 (m,1H), 3.27-3.18 (m, 2H), 3.04 (s, 3H), 2.99-2.85 (m, 2H), 2.41-2.30 (m,4H), 2.22-1.95 (m, 3H), 1.11 (d, J=6.6 Hz, 3H), LCMS m/z=593.3[M+H]⁺.

Example 14

Step 1: Synthesis of Compound 14-2

N,N-dimethylformamide (4 mL) was added to a dry reaction flask, followedby compound 10-2 (220 mg, 288.82 μmol, 1 eq), compound 14-1 (123.79 mg,577.64 μmol, 2 eq) and N,N-diisopropylethylamine (111.98 mg, 866.45μmol, 150.92 μL, 3 eq). The mixture was stirred. The reaction system wasstirred at 50° C. for 1 hr. The reaction solution was extracted withethyl acetate (30 mL). The organic phase solution was collected, washedonce with saturated ammonium chloride solution (15 mL) and once withsaturated brine (15 mL), dried with anhydrous sodium sulfate andfiltered. Then the filtrate was concentrated under reduced pressure togive a crude product of compound 14-2, which was used directly in thenext step without purification. LCMS m/z=826.3 [M+H]⁺.

Step 2: Synthesis of Compound 14-3

Dichloromethane (10 mL) was added to a dry reaction flask, followed bycompound 14-2 (350.18 mg, 423.97 μmol, 1 eq), and the mixture wasstirred. m-Chloroperoxybenzoic acid (109.75 mg, 508.77 μmol, 80% purity,1.2 eq) was added and the reaction system was stirred at 25° C. for 1 h.A more polar main spot was detected. The reaction solution was dilutedwith dichloromethane (10 mL), then washed once with 5% sodiumthiosulfate (10 mL) and once with saturated brine (10 mL), dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give a crude product. The crude product waspurified by column (petroleum ether:ethyl acetate=90:10 to 50:50)according to TLC (petroleum ether:ethyl acetate=0:1) to give compound14-3. LCMS m/z=842.3[M+H]⁺.

Step 3: Synthesis of Compound 14-4

Toluene (5 mL) was added to a dry reaction flask, and then compound1-11A (98.73 mg, 857.24 μmol, 4.5 eq) was added and stirred. Then sodiumtert-butoxide (82.38 mg, 857.24 μmol, 4.5 eq) was added, and thereaction system was cooled down to 0° C. and stirred for 10 min. Asolution of compound 14-3 (160.39 mg, 190.50 μmol, 1 eq) in toluene (2mL) was added, and the reaction system was stirred at 0 C for 1 h. Thereaction mixture was combined with the batch of compound 14-3 (50 mg)for treatment. The reaction solution was extracted with ethyl acetate(30 mL). The organic phase solution was collected, washed once withsaturated ammonium chloride solution (10 mL) and once with saturatedbrine (10 mL), dried with anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure to give a crude productof compound 14-4, which was used directly in the next step withoutpurification. LCMS m/z=893.4[M+H]⁺.

Step 4: Synthesis of Compound 14-5

Dichloromethane (5 mL) was added to a dry reaction flask and thencompound 14-4 (260 mg, 291.15 μmol, 1 eq) was added. The mixture wasstirred. Trifluoroacetic acid (2.77 g, 24.31 mmol, 1.8 mL, 83.50 eq) wasadded and the reaction system was stirred at 20° C. for 2 hr. Thereaction solution was diluted with dichloromethane (20 mL), and thenwater (20 mL) was added. The layers were separated. The aqueous phasewas adjusted to pH of 8 with saturated sodium bicarbonate, and thenextracted with ethyl acetate (20 mL×2). The organic phases werecombined, washed with saturated brine (10 mL), dried with anhydroussodium sulfate, and filtered. The filtrate was concentrated underreduced pressure to give a crude product of compound 14-5, which wasdirectly used in the next step without purification. LCMSm/z=553.2[M+H]⁺.

Step 5: Synthesis of Compound 14

Dichloromethane (5 mL) was added to a dry reaction flask, followed byacrylic acid (10.56 mg, 146.58 μmol, 10.06 μL, 1 eq), compound 14-5 (90mg, 146.58 μmol, 90% purity, 1 eq) and N,N-diisopropylethylamine (56.83mg, 439.73 μmol, 76.59 μL, 3 eq). The mixture was stirred and thereaction system was cooled down to −60° C.O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (66.88 mg, 175.89 μmol, 1.2 eq) was added. Themixture was then stirred for 0.5 h. The reaction was quenched by addingwater (5 mL) and the layers were separated. The organic phase was driedwith anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure to give a crude product. The crudeproduct was purified by a high-performance liquid chromatography column{column: Welch Xtimate C18 100*25 mm*3 μm; mobile phase: [H₂O(0.05%HCl)-ACN]; acetonitrile %: 15%-45%, 8 min} to give compound 14. ¹H NMR(400 MHz, CDCl₃) 6.69-6.62 (m, 1H), 6.62-6.48 (m, 1H), 6.47-6.34 (m,1H), 5.91-5.76 (m, 1H), 5.34 (s, 1H), 5.25-5.14 (m, 1H), 5.10-4.99 (m,1H), 4.86-4.64 (m, 2H), 4.62-4.30 (m, 2H), 4.21-4.11 (m, 1H), 4.06-3.93(m, 2H), 3.90-3.73 (m, 2H), 3.71-3.59 (m, 1H), 3.57-3.49 (m, 3H),3.47-3.33 (m, 1H), 3.28-3.15 (m, 2H), 3.09-2.92 (m, 1H), 2.50-2.35 (m,4H), 2.26-2.09 (m, 2H), 1.43-1.32 (m, 4H), 1.31-1.25 (m, 2H), LCMSm/z=607.4[M+H]⁺.

Example 15

Step 1: Synthesis of Compound 15-2

N,N-dimethylformamide (3 mL) was added to a dry reaction flask andcompound 10-2 (200 mg, 262.56 μmol, 1 eq) was added. The mixture wasstirred. N,N-diisopropylethylamine (101.80 mg, 787.69 μmol, 137.20 μL, 3eq) and compound 15-1 (78.88 mg, 393.84 μmol, 1.5 eq) were added. Thereaction system was reacted at 50° C. for 30 min. The mixture wascombined with the batch of compound 10-2 (10 mg) for treatment. Thereaction solution was poured into saturated aqueous ammonium chloride (5mL) and extracted with ethyl acetate (5 mL×3). The organic phases werecombined, washed with saturated brine, dried with anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure to give a crude product of compound 15-2, which was useddirectly in the next step without purification. LCMS m/z=812.2[M+H]⁺.

Step 2: Synthesis of Compound 15-3

Dichloromethane (3 mL) was added to a dry reaction flask, and thencompound 15-2 (0.24 g, 295.59 μmol, 1 eq) was added. The mixture wasstirred. m-Chloroperoxybenzoic acid (66.95 mg, 310.37 μmol, 80% purity1.05 eq) was added and the reaction system was reacted at 25° C. for 30min. The reaction solution was quenched with aqueous sodium sulfite (5mL 5%). The layers were separated. The aqueous phase was extracted withdichloromethane (5 mL×2). The organic phases were combined, dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give a crude product. The aqueous phase wasdetected with starch-potassium iodide test paper, and showednon-oxidative. The aqueous phase was discarded. The crude product waspurified by column chromatography (petroleum ether:ethyl acetate=50:1 to0:1) according to TLC (petroleum ether:ethyl acetate=1:1, productRf=0.51) to give compound 15-3. ¹H NMR (400 MHz, CDCl₃) δ=7.17-7.06 (m,4H), 6.83-6.72 (m, 4H), 6.71-6.60 (m, 1H), 5.24-5.10 (m, 1H), 4.87-4.64(m, 2H), 4.44-4.17 (m, 4H), 3.98-3.81 (m, 2H), 3.78-3.69 (m, 6H),3.67-3.43 (m, 2H), 3.20-2.97 (m, 4H), 2.88-2.78 (m, 3H), 2.32-2.20 (m,3H), 1.47-1.37 (m, 9H), 1.32-1.23 (m, 3H). LCMS m/z=828.3 M+H]⁺.

Step 3: Synthesis of Compound 15-4

Toluene (1 mL) was added to a dry reaction flask, and compound 15-3 (180mg, 217.41 μmol, 1 eq) was added. The mixture was stirred. The reactionsystem was cooled down to 0-5° C., and sodium tert-butoxide (2.68 mg,652.23 μmol, 3 eq) was added. The mixture was stirred for 10 min. Asolution of compound 1-11A (75.12 mg, 652.23 μmol, 77.44 μL, 3 eq) intoluene (0.3 mL) was added to the above reaction solution and thereaction system was reacted at 0 to 5° C. for 30 min. The reactionsolution was poured into saturated aqueous ammonium chloride (5 mL) andextracted with ethyl acetate (5 mL×3). The organic phases were combined,washed with saturated brine (5 mL), dried with anhydrous sodium sulfate,and filtered. The filtrate was concentrated under reduced pressure togive a crude product of compound 15-4, which was used directly in thenext step without purification. LCMS m/z=879.4[M+H]⁺.

Step 4: Synthesis of Compound 15-5

Dichloromethane (4 mL) was added to a dry reaction flask, and compound15-4 (160 mg, 182.03 μmol, 1 eq) was added. The mixture was stirred. Thereaction system was cooled down to 0-5° C. Trifluoroacetic acid (1.23 g,10.81 mmol, 800.00 μL, 59.36 eq) was added, and the mixture was stirredfor 4 hours. The reaction solution was added to saturated aqueous sodiumbicarbonate (10 mL). The layers were separated. The mixture wasextracted with dichloromethane (5 mL×2). The organic phases werecombined, dried with anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under reduced pressure to give a crude productof compound 15-5, which was used directly in the next step withoutpurification. LCMS m/z=539.2[M+H]⁺.

Step 5: Synthesis of Compound 15

Dichloromethane (10 mL) was added to a dry reaction flask, and thencompound 15-5 (0.06 g, 111.40 μmol, 1 eq) and acrylic acid (16.06 mg,222.81 μmol, 15.29 μL, 2 eq) were added. The mixture was stirred. ThenN,N-diisopropylethylamine (28.80 mg, 222.81 μmol, 38.81 μL, 2 eq) wasadded, and the reaction system was cooled down to −60° C.O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (63.54 mg, 167.11 μmol, 1.5 eq) was added and thereaction system was reacted at −60° C. for 0.5 h. The mixture wascombined with the batch of compound 15-5 (20 mg) for treatment.Dichloromethane (5 mL) was added to the reaction solution. The reactionsolution was washed with saturated ammonium chloride solution (5 mL×2),dried with anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to give a crude product. The crudeproduct was purified by a high-performance liquid chromatography column{column: Phenomenex Luna C18 200*40 mm*10 μm; mobile phase: [H₂O(0.04%HCl)-ACN]; acetonitrile %: 1%-50%, 8 min}. One drop of ammonia water wasadded to the fraction solution, and the solution showed alkaline. Thesolution was concentrated to remove the organic solvent and lyophilizedto give compound 15. ¹H NMR (400 MHz, CD₃OD) δ=7.24-7.07 (m, 2H), 6.80(dd, J=10.8, 16.8 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 6.24 (d, J=16.8 Hz,1H), 5.79 (d, J=11.7 Hz, 1H), 5.24-5.16 (m, 1H), 4.76 (d, J=13.8 Hz,3H), 4.57 (dd, J=7.2, 12.5 Hz, 2H), 4.07-3.86 (m, 3H), 3.73 (s, 1H),3.17 (d, J=11.4 Hz, 3H), 3.07 (s, 3H), 2.90 (d, J=14.8 Hz, 1H),2.46-2.34 (m, 4H), 2.33-2.30 (m, 1H), 2.26-1.95 (m, 3H), 1.41 (s, 3H).LCMS m/z=593.2[M+H]⁺.

Example 16

Step 1: Synthesis of Compound 16-2

N,N-dimethylformamide (3 mL) was added to a dry reaction flask, andcompound 10-2 (200 mg, 262.56 μmol, 1 eq) was added. The mixture wasstirred. N,N-diisopropylethylamine (101.80 mg, 787.69 μmol, 137.20 μL, 3eq) and compound 16-1 (78.02 mg, 393.84 μmol, 1.5 eq, 2HCl) were added,and the reaction system was reacted at 50° C. for 30 min. The mixtureswere combined for treatment. The reaction solution was poured intosaturated aqueous ammonium chloride (15 mL) and extracted with ethylacetate (10 mL×3). The organic phases were combined, washed withsaturated brine (20 mL), dried with anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to give acrude product of compound 16-2, which was used directly in the next stepwithout purification. LCMS m/z=737.2 [M+H]⁺.

Step 2: Synthesis of Compound 16-3

N,N-dimethylformamide (3 mL) was added to a dry reaction flask, andcompound 16-2 (230 mg, 312.15 μmol, 1 eq) was added. The mixture wasstirred. N,N-diisopropylethylamine (121.03 mg, 936.46 μmol, 163.11 μL, 3eq) and di-tert-butyl dicarbonate (74.94 mg, 343.37 μmol, 78.88 μL, 1.1eq) were added, and the reaction system was reacted at 20° C. for 10 h.The reaction solution was poured into saturated aqueous ammoniumchloride (15 mL) and extracted with ethyl acetate (10 mL×2). The organicphases were combined, washed with saturated brine (5 mL), dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give a crude product. The crude product waspurified by column chromatography (petroleum ether:ethylacetate=100:1-0:1) according to TLC (petroleum ether:ethyl acetate=3:1)to give compound 16-3. ¹H NMR (400 MHz, CDCl₃) δ=7.16 (d, J=8.4 Hz, 4H),6.85 (d, J=8.6 Hz, 4H), 6.64 (d, J=8.0 Hz, 1H), 5.22 (d, J=7.2 Hz, 1H),4.90-4.68 (m, 2H), 4.61 (s, 1H), 4.41-4.21 (m, 4H), 4.04 (s, 1H), 3.80(s, 6H), 3.71 (s, 1H), 3.50 (d, J=11.0 Hz, 2H), 3.30 (s, 1H), 3.24-3.02(m, 2H), 2.90 (d, J=2.0 Hz, 1H), 2.78-2.58 (m, 2H), 2.55 (s, 3H), 2.34(d, J=4.0 Hz, 3H), 1.51 (s, 9H). LCMS m/z=837.2[M+H]⁺.

Step 3: Synthesis of Compound 16-4

Dichloromethane (0.3 mL) was added to a dry reaction flask, and compound16-3 (230 mg, 274.81 μmol, 1 eq) was added. The mixture was stirred.m-Chloroperoxybenzoic acid (61.37 mg, 302.29 μmol, 85% purity, 1.1 eq)was added, and the reaction system was reacted at 20° C. for 1 hour. Thereaction solution was poured into 5% aqueous sodium sulfite solution (5mL) and the layers were separated. The aqueous phase was extracted withdichloromethane (5 mL×2). The organic phases were combined, dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give a crude product. The aqueous phase wastested with starch-potassium iodide test paper, and showednon-oxidative. The aqueous phase was discarded. The crude product waspurified by column chromatography (petroleum ether:ethylacetate=100:1-0:1) according to TLC (petroleum ether:ethyl acetate=1:1)to give compound 16-4. LCMS m/z=853.2[M+H]⁺.

Step 4: Synthesis of Compound 16-5

Toluene (2 mL) was added to a dry reaction flask, and compound 16-4 (158mg, 185.24 μmol, 1 eq) was added. The mixture was stirred. The reactionsystem was cooled down to 0° C. Sodium tert-butoxide (35.60 mg, 370.49μmol, 2 eq) was added. The mixture was stirred for 15 min, and compound12-3A (65.40 mg, 463.11 μmol, 2.5 eq) was added. The reaction system wasreacted at 0° C. for 30 min. The reaction solution was poured intosaturated aqueous ammonium chloride (5 mL) and extracted with ethylacetate (5 mL×3). The organic phases were combined, washed withsaturated brine (3 mL), dried with anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to give acrude product of compound 16-5, which was used directly in the next stepwithout purification. LCMS m/z=930.4 [M+H]⁺.

Step 5: Synthesis of Compound 16-6

Dichloromethane (5 mL) was added to a dry reaction flask, and compound16-5 (0.18 g, 193.54 μmol, 1 eq) was added. The mixture was stirred.Then trifluoroacetic acid (1 mL) was added and the reaction system wasreacted at 18° C. for 3 hours. Water (10 mL) was added to the reactionsolution, and the mixture was extracted. The layers were separated. Theaqueous phase was collected, adjusted to pH of 8 with saturated sodiumbicarbonate solution, and extracted with dichloromethane (20 mL×2). Theorganic phases were combined, dried with anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to give acrude product of compound 16-6, which was used directly in the next stepwithout purification. LCMS m/z=590.2[M+H]⁺

Step 6: Synthesis of Compound 16

Compound 16-6 (62.77 mg, 106.46 μmol, 1 eq), 2-fluoroacrylic acid (19.17mg, 212.92 μmol, 2 eq), and N,N-diisopropylethylamine (41.28 mg, 319.38μmol, 55.63 μL, 3 eq) were dissolved in DCM (5 mL), and the mixture wascooled down to −60° C.O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (48.58 mg, 127.75 μmol, 1.2 eq) was added. Themixture was stirred for 0.5 hr. The reaction solution was combined withthe batch of compound 16-6 (20.92 mg) for treatment. 5 mL of water wasadded to the reaction solution. The layers were separated. The organicphase was concentrated, and purified by a high-performance liquidchromatography column {column: Phenomenex luna C18 80*40 mm*3 μm; mobilephase: [H₂O(0.04% HCl)-ACN]; acetonitrile %: 20%-40%, 7 min} to givecompound 16. ¹H NMR (400 MHz, CD₃OD) δ=6.73 (d, J=8.6 Hz, 1H), 5.45-5.21(m, 3H), 4.87-4.80 (m, 2H), 4.57 (s, 2H), 4.19 (br d, J=13.7 Hz, 1H),3.98 (br d, J=13.1 Hz, 1H), 3.75-3.66 (m, 2H), 3.56-3.49 (m, 1H), 3.37(s, 3H), 3.32-3.27 (m, 2H), 3.26-3.11 (m, 1H), 3.06-2.87 (m, 1H),3.06-2.87 (m, 1H), 3.06-2.87 (m, 1H), 2.44-2.03 (m, 12H). LCMSm/z=662.4[M+H]⁺.

Example 17

Step 1: Synthesis of Compound 17-2

N,N-dimethylformamide (30 mL) was added to a dry reaction flask, andthen compound 10-2 (2.8 g, 3.68 mmol, 1 eq) was added. The mixture wasstirred. N,N-diisopropylethylamine (1.43 g, 11.03 mmol, 1.92 mL, 3 eq)and compound 16-1 (873.80 mg, 4.41 mmol, 1.2 eq, 2HCl) were added, andthe reaction system was reacted at 50° C. under nitrogen for 1 h. Themixture was combined with the batch of compound 10-2 (0.2 g) fortreatment. Methyl tert-butyl ether (30 mL) was added to the reactionsolution, and the mixture was washed twice with saturated ammoniumchloride solution (30 mL×2) and twice with saturated brine (30 mL×2),dried with anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure to give a crude product of compound17-2, which was used directly in the next step without purification. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.15 (d, J=8.80 Hz, 4H), 6.84 (d, J=8.40 Hz,4H), 6.63 (d, J=8.40 Hz, 1H), 5.22 (dd, J=11.20, 4.00 Hz, 1H), 4.71 (s,2H), 4.36-4.20 (m, 4H), 4.06 (d, J=12.80 Hz, 1H), 3.80 (s, 6H),3.61-3.50 (m, 2H), 3.43 (dd, J=18.80, 11.60 Hz, 2H), 3.27-3.15 (m, 2H),3.12-2.98 (m, 2H), 2.85-2.66 (m, 2H), 2.53 (s, 3H), 2.38-2.31 (m, 3H),LCMS m/z=737.2[M+H]⁺.

Step 2: Synthesis of Compound 17-3

Dichloromethane (25 mL) was added to a dry reaction flask and compound17-2 (2.3 g, 3.12 mmol, 1 eq) was added. The mixture was stirred. Thereaction system was cooled down to 0° C. Triethylamine (789.67 mg, 7.80mmol, 1.09 mL, 2.5 eq) and trifluoroacetic anhydride (983.42 mg, 4.68mmol, 651.27 μL, 1.5 eq) were added, and the reaction system was reactedat 0 to 5° C. for 0.5 hr. The mixture was combined with the batch ofcompound 17-2 (0.3 g) for treatment. The reaction solution was washedwith a saturated ammonium chloride solution (20 mL×2), dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give a crude product of compound 17-3, whichwas used directly in the next step without purification. ¹H NMR (400MHz, CDCl₃) δ ppm 7.15 (d, J=8.40 Hz, 4H), 6.84 (d, J=8.40 Hz, 4H), 6.65(br d, J=8.40 Hz, 1H), 5.29-5.20 (m, 1H), 4.77 (s, 2H), 4.38-4.24 (m,4H), 4.05-3.88 (m, 2H), 3.80 (s, 6H), 3.78-3.60 (m, 2H), 3.59-3.37 (m,2H), 3.14-2.99 (m, 2H), 2.98-2.93 (m, 1H), 2.91-2.86 (m, 1H), 2.78 (t,J=6.80 Hz, 1H), 2.53 (s, 3H), 2.39-2.30 (m, 3H), LCMS m/z=833.1 [M+H]⁺.

Step 3: Synthesis of Compound 17-4

Dichloromethane (30 mL) was added to a dry reaction flask, and compound17-3 (2.6 g, 3.12 mmol, 1 eq) was added. The mixture was stirred.m-Chloroperoxybenzoic acid (697.20 mg, 3.43 mmol, 85% purity, 1.1 eq)was added, and the reaction system was reacted at 18° C. for 0.5 h. Thereaction system was combined with the batch of compound 17-3 (0.2 g) fortreatment. Sodium thiosulfate solution (20 mL 10%) was added to thereaction solution, and the mixture showed negative by starch-KI paper.The mixture was extracted with dichloromethane (20 mL×2), dried withanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder reduced pressure to give a crude product, which was purified bycolumn (petroleum ether:ethyl acetate=10:1-0:1) according to TLC(petroleum ether:ethyl acetate=0:1) to give compound 17-4. ¹H NMR (400MHz, CDCl₃) δ ppm 7.15 (d, J=8.40 Hz, 4H), 6.84 (d, J=8.40 Hz, 4H), 6.66(d, J=8.40 Hz, 1H), 5.27 (d, J=9.20 Hz, 1H), 4.93-4.982 (m, 2H),4.38-4.24 (m, 4H), 4.10-3.99 (m, 2H), 3.98-3.88 (m, 1H), 3.87-3.68 (m,8H), 3.67-3.54 (m, 1H), 3.54-2.98 (m, 3H), 2.93-2.79 (m, 4H), 2.78-2.65(m, 1H), 2.35 (d, J=3.60 Hz, 3H), LCMS m/z=849.1 [M+H]⁺.

Step 4: Synthesis of Compound 17-5

Toluene (1 mL) was added to a dry reaction flask, and compound 17-4A(78.77 mg, 494.80 μmol, 3 eq) was added. The mixture was stirred. thereaction system was cooled down to 0° C., and sodium tert-butoxide(47.55 mg, 494.80 μmol, 3 eq) was added. The mixture was stirred for 10min, and then a solution of compound 17-4 (0.14 g, 164.93 μmol, 1 eq) intoluene (0.5 mL) was added. The mixture was reacted for another 0.5 h.The reaction system was combined with the batch of compound 17-4 (20 mg)for treatment. The reaction solution was diluted with ethyl acetate (5mL), washed sequentially with saturated ammonium chloride (10 mL×2) andsaturated brine (10 mL), dried with anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to give acrude product of compound 17-5, which was used directly in the next stepwithout purification. LCMS m/z=848.3[M+H]⁺.

Step 5: Synthesis of Compound 17-6

Dichloromethane (12 mL) was added to a dry reaction flask, and thencompound 17-5 (160.00 mg, 188.70 μmol, 1 eq) was added. The mixture wasstirred. Then trifluoroacetic acid (2 mL) was added, and the reactionsystem was reacted at 18° C. for 2 h. The reaction system was combinedwith the batch of compound 17-5 (20 mg) for treatment. Water (10 mL) wasadded to the reaction solution. The layers were separated afterextraction. The aqueous phase was adjusted to pH of 8 with saturatedsodium bicarbonate solution, and extracted with dichloromethane (10mL×2). The organic phases were combined, dried with anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure to give a crude product of compound 17-6, which was useddirectly in the next step without purification. LCMS m/z=608.3 [M+H]⁺.

Step 6: Synthesis of Compound 17

Dichloromethane (5 mL) was added to a dry reaction flask, and thencompound 17-6 (50 mg, 82.29 μmol, 1 eq), 2-fluoroacrylic acid (14.82 mg,164.58 μmol, 2 eq), and N,N-diisopropylethylamine (31.90 mg, 246.87μmol, 43.00 μL, 3 eq) were added. The mixture was stirred. The reactionsystem was cooled down to −60° C. andO-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (37.55 mg, 98.75 μmol, 1.2 eq) was added. Themixture was then stirred for 0.5 h. The mixtures were combined fortreatment. The reaction mixture was quenched by adding water (5 mL) tothe reaction solution and the layers were separated. The organic phasewas dried with anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure to give a crude product, which waspurified by a high-performance liquid chromatography column {column:Welch Xtimate C18 100*25 mm*3 μm; mobile phase: [H₂O(0.05% HCl)-ACN];acetonitrile %: 20%-50%, 8 min} to give compound 17. SFC analysis method(column: Chiralcel OD-3, 50×4.6 mm I.D., 3 μm; Mobile phase: A (CO2) andB (methanol, containing 0.05% diisopropylamine); Gradient: B %=5-50%, 3min; Flow rate: 3.4 mL/min; Wavelength: 220 nm; Pressure: 1800 psi,Optical purity: 99.21%, time-to-peak: 1.840). ¹H NMR (400 MHz, CD₃OD)δ=6.80-6.68 (m, 1H), 5.73-5.51 (m, 1H), 5.46-5.19 (m, 3H), 5.05-4.90 (m,3H), 4.74-4.58 (m, 2H), 4.37-4.26 (m, 1H), 4.20-4.06 (m, 2H), 4.05-3.84(m, 3H), 3.79-3.59 (m, 2H), 3.54-3.43 (m, 1H), 3.42-3.35 (m, 1H),3.31-3.24 (m, 1H), 3.13-2.89 (m, 3H), 2.82-2.52 (m, 2H), 2.50-2.42 (m,1H), 2.41-2.30 (m, 5H), 2.29-2.18 (m, 1H).

Example 18

Step 1: Synthesis of Compound 18-1

1-11A (194.75 mg, 1.69 mmol, 200.78 μL, 4 eq) was added to anhydroustoluene (16 mL). The mixture was cooled down to 0° C., and sodiumtert-butoxide (162.50 mg, 1.69 mmol, 4 eq) was added. The mixture wasreacted at 0 to 5° C. for 10 min. A solution of compound 9-3 (0.35 g,422.74 μmol, 1 eq) in toluene (5 mL) was added, and the mixture wasreacted at 0 to 5° C. for 0.5 h. The mixture was combined with the batchof compound 9-3 (50 mg) for treatment. The reaction solution was washedwith 20 mL×2 of saturated ammonium chloride and 20 mL of saturatedbrine, dried with anhydrous sodium sulfate, and filtered. The filtratewas concentrated to give compound 18-1. MS m/z=879.2[M+H]⁺.

Step 2: Synthesis of Compound 18-2

Compound 18-1 (0.4 g, 455.07 μmol, 1 eq) was added to anhydrousdichloromethane (12 mL), and trifluoroacetic acid (2.4 mL) was added.The mixture was reacted at 25° C. for 1.5 h. The mixture was combinedwith the batch of compound 18-1 (50 mg) for treatment. Saturated sodiumbicarbonate was slowly added to the reaction solution until pH was 7-8.The mixture was extracted with 20 mL of dichloromethane, dried withanhydrous sodium sulfate, and filtered. The filtrate was thenconcentrated to dryness by rotary evaporation to give compound 18-2.LCMS m/z=539.1 [M+H]⁺

Step 5: Synthesis of Compounds 18A and 18B

Compound 18-2 (36.80 mg, 510.60 μmol, 35.04 μL, 1.1 eq), acrylic acid(36.80 mg, 510.60 μmol, 35.04 μL, 1.1 eq) and N,N-diisopropylethylamine(179.97 mg, 1.39 mmol, 242.55 μL, 3 eq) were added to anhydrousdichloromethane (5 mL). The mixture was cooled down to −60° C., andO-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (176.50 mg, 464.18 μmol, 1 eq) was added. Themixture was reacted at −60° C. for 30 min. The reaction solution wasdiluted with 10 mL of dichloromethane, washed with 10 mL×2 of saturatedammonium chloride, dried with anhydrous sodium sulfate, and filtered.The filtrate was then concentrated. The residue was purified by ahigh-performance liquid chromatography column (column: Phenomenex lunaC18 100*40 mm*5 μm; mobile phase: [H₂O(0.1% TFA)-ACN]; acetonitrile %:10%-40%, 8 min), lyophilized, and then subjected to chiral separationaccording to SFC (column: DAICEL CHIRALCEL OD(250 mm*30 mm, 10 μm);mobile phase: [0.1%₀NH₃H₂O ETOH]; ethanol %: 50%-50%, 15 min) to givecompound 18A ((chiral time-to-peak: 1.479). SFC resolution method(column: Chiralcel OD-3, 50×4.6 mm I.D., 3 μm; Mobile phase: A (CO₂) andB (methanol, containing 0.05% diisopropylamine); Gradient: B %=5-50%, 3min; Flow rate: 3.4 mL/min; Wavelength: 220 nm; Pressure: 1800 psi,Optical purity 100%). MS m/z=593.3[M+H]⁺, ¹H NMR (400 MHz, CDCl₃)δ=6.66-6.50 (m, 2H), 6.36 (d, J=16.8 Hz, 1H), 5.76 (d, J=10.0 Hz, 1H),5.20 (d, J=7.6 Hz, 1H), 4.58-4.53 (m, 1H), 4.45-4.20 (m, 2H), 4.01 (s,3H), 3.85-3.23 (m, 6H), 3.04-2.86 (m, 2H), 2.67 (s, 2H), 2.47-2.33 (m,3H), 2.22-1.53 (m, 8H), 1.23-1.04 (m, 3H)) and compound 18B ((chiraltime-to-peak: 1.642), SFC resolution method (column: Chiralcel OD-3,50×4.6 mm I.D., 3 μm; Mobile phase: A (CO₂) and B (methanol, containing0.05% diisopropylamine); Gradient: B %=5-50%, 3 min; Flow rate: 3.4mL/min; Wavelength: 220 nm; Pressure: 1800 psi, Optical purity 97.8%).LCMS m/z=593.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=6.72-6.48 (m, 2H), 6.35(dd, J=1.6, 16.8 Hz, 1H), 5.76 (d, J=10.4 Hz, 1H), 5.20 (d, J=7.6 Hz,1H), 4.83-4.57 (m, 3H), 4.18-3.99 (m, 3H), 3.94-3.51 (m, 2H), 3.50-3.20(m, 2H), 3.11-2.75 (m, 6H), 2.43-2.35 (m, 3H), 2.35-1.80 (m, 8H), 1.38(d, J=6.4 Hz, 3H)).

Example 19

Step 1: Synthesis of Compound 19

Dichloromethane (5 mL) was added to a dry reaction flask, and thencompound 17-6 (25 mg, 42.40 μmol, 1 eq), acrylic acid (6.11 mg, 84.80μmol, 5.82 μL, 2 eq) and N,N-diisopropylethylamine (16.44 mg, 127.20μmol, 22.16 μL, 3 eq) were added. The mixture was stirred. The reactionsystem was cooled down to 0° C., andO-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (19.35 mg, 50.88 μmol, 1.2 eq) was added. Themixture was stirred at 20° C. for 3 hr. The reaction was quenched byadding water (5 mL) to the reaction solution and the layers wereseparated. The organic phase was dried with anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure to give acrude product, which was purified by a high-performance liquidchromatography column {column: Phenomenex luna C18 80*40 mm*3 μm; mobilephase: [H₂O(0.04% HCl)-ACN]; B %: 18%-34%, 7 min} to give compound 19.LCMS m/z=622.2[M+H]⁺.

Example 20

Step 1: Preparation of Intermediate 20-1

Compound 9-2 (90 mg, 110.85 μmol) was dissolved in dichloromethane (2mL) and m-chloroperoxybenzoic acid (45.01 mg, 221.70 μmol, 85% content)was added. The reaction solution was stirred at 20° C. for another 3 h.The organic solvent was removed under reduced pressure, and theresulting crude product was purified by preparative thin layerchromatography plate (developer: dichloromethane:methanol=20:1) to givecompound 20-1. MS m/z=844.4 [M+H]⁺.

Step 2: Preparation of Intermediate 20-2

Compound 17-4A (12.26 mg, 77.02 μmol) was dissolved in anhydroustetrahydrofuran (2 mL) at 20° C. Sodium tert-butoxide (7.40 mg, 77.02μmol) was added and the reaction solution was stirred for another 30min. A solution of compound 20-1 (50 mg, 59.25 μmol) in tetrahydrofuran(0.5 mL) was added and the reaction solution was stirred at thistemperature for 0.5 h. The organic solvent was removed under reducedpressure and the resulting crude product was purified by preparativethin layer chromatography plate (developer:dichloromethane:methanol=10:1) to give compound 20-2. MS m/z=923.6[M+H]⁺.

Step 3: Preparation of Compound 20-3

Compound 20-2 (45 mg, 48.75 μmol) was dissolved in anhydrousdichloromethane (2 mL), and trifluoroacetic acid (1.5 mL) was added. Thereaction solution was stirred at 20° C. for another 2 h. The solvent wasremoved under reduced pressure, and the resulting crude product wasdissolved in 20 mL of dichloromethane. 3 g of solid sodium bicarbonatewas added, and the mixture was stirred at room temperature for another 1h. The mixture was filtered, and the organic solvent was removed underreduced pressure to give a crude product of 20-3, which was useddirectly in the next reaction step without further purification.

Step 5: Preparation of Compound 20

Compound 20-3 (20 mg, 34.33 μmol) was dissolved in anhydrousdichloromethane (2 mL) at 20° C. Diisopropylethylamine (13.31 mg, 102.99μmol, 17.94 μL) and acryloyl chloride (4.66 mg, 51.49 μmol, 4.20 μL)were added, and the reaction solution was stirred at this temperaturefor another 16 hr. The organic solvent was removed under reducedpressure and the crude product was purified by high-performance liquidchromatography (column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase:[water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile:22%-52%, 8 min) to give the trifluoroacetate salt of compound 20. MSm/z=637.4 [M+H]⁺.

Biological Assay Data: Assay Example 1: Assay of Inhibitory Effect ofCompounds on the Proliferation of KRAS^(G12C)-Mutated MIA-PA-CA-2 Cells

1.1 Purpose of the Assay

Compounds were assayed for IC₅₀ of inhibition of proliferation ofKRAS^(G12C)-mutated MIA-PA-CA-2 cells.

1.2 Reagent

The main reagent used in this assay included CellTiter-Glo (Promega,Cat. No. G7573).

1.3 Instrument

The main instrument used in this assay was PerkinElmer EnVisionmulti-function microplate reader.

1.4 Method of the Assay

1) Adherent cells were digested with trypsin to form a cell suspension,and the cell suspension was counted for later use.2) An appropriate amount of cells was added into a centrifuge tube, anda cell culture medium was added to make up the required volume; then thecells were plated to a 96-well plate at a final density of 2000cells/well, 100 μL of culture medium.3) After incubating for 24 hr, the compound was formulated to 10 mM withDMSO, and serially diluted 3-fold with DPBS (Dulbecco's PhosphateBuffered Saline) to 9 points; 10 μL was added to each well in duplicate.10 μL of DPBS per well was added to the assay control wells (Con).4) On the same day, 50 μL of CellTiter Glo was added to another cellculture plate without compounds, and the fluorescence value was read byEnVision. The value was marked as Day 0 value.5) After 72 h incubation of cells treated with compounds, the plate wasremoved, and 50 μL of CellTiter Glo was added to the cell plate. Thefluorescence value was read by EnVision.6) Data analysis: The inhibition rate of cells in each well wascalculated according to the following equation:

${{Inhibition}{rate}\%} = {( {1 - \frac{FCpd}{{FCon} - {{FDay}0}}} )*100\%}$

* F_(Day0) was the reading value of the original cell number assay wellwithout compound treatment;F_(con) was the fluorescence reading value of the Con group after 72 hrof incubation.F_(Cpd) was the fluorescence reading value of each compound well after72 hr of incubation.7) Log(agonist) vs. response—Variable slope nonlinear fit analysis onthe inhibition rate data (inhibition rate %) of compounds was performedto give IC₅₀ values of compounds by GraphPad Prism software using thefollowing equation:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC₅₀−X)*HillSlope))

1.5 Results of the Assay

TABLE 1 Assay results of compounds of the present disclosure on theinhibition of proliferation of KRAS^(G12C)-mutated MIA-PA-CA-2 cellsCompound No. IC₅₀ (nM)  1 5.21  8B hydrochloride 2.7  9B 6.98 12 1.30 162.22 17 0.44 18B 3.29

The assay results showed that the compounds of the present disclosurehave good inhibitory activity on cell proliferation ofKRAS^(G12C)-mutated MIA-PA-CA-2 cell line.

Assay Example 2: H358 Cell Assay

2.1 Purpose of the Assay

Compounds were assayed for IC₅₀ of inhibition of proliferation ofKRAS^(G12C)-mutated H358 cells.

2.2 Reagent

The main reagents used in this assay included RPMI-1640 medium,penicillin/streptomycin antibiotics purchased from Vicente, fetal bovineserum purchased from Biosera, CellTiter-Glo (cell viabilitychemiluminescence detection reagent) reagent purchased from Promega, andNCI-H358 cell line purchased from the Cell Bank of the Chinese Academyof Sciences.

2.3 Instrument

The main instrument used in this assay was a Nivo multi-label analyzer(PerkinElmer).

2.4 Method of the Assay:

1) NCI-H358 cells were inoculated in a white 96-well plate, and eachwell contained 80 μL of cell suspension and 4000 NCI-H358 cells. Thecell plate was incubated in a carbon dioxide incubator overnight.2) The compounds to be assayed were serially diluted 5-fold with amulti-channel pipette to obtain nine concentrations, i.e., from 2 mM to5.12 nM. The assay was carried out in duplicate. 78 μL of medium wasadded to the intermediate plate, and then 2 μL of the serially dilutedcompound was transferred to each well of the intermediate plateaccording to the corresponding position. After mixing well, 20 μL perwell was transferred to the cell plate. The concentrations of compoundstransferred to the cell plate ranged from 10 μM to 0.0256 nM. The cellplate was incubated in a carbon dioxide incubator for 5 days. Anothercell plate was prepared, and the signal value of the cell plate was readon the day of compound addition as the maximum value (Max value in theequation below) to participate in data analysis. 25 μL of cell viabilitychemiluminescence detection reagent was added to each well of the cellplate, and the plate was incubated at room temperature for 10 minutes tostabilize the luminescence signal. A multi-label analyzer was used forreading the plate.3) 25 μL of cell viability chemiluminescence detection reagent was addedto each well of the cell plate, and the plate was incubated at roomtemperature for 10 minutes to stabilize the luminescence signal. Amulti-label analyzer was used for reading the plate.

Data Analysis:

The equation (Sample−Min)/(Max−Min)*100% was used to convert the rawdata into inhibition rate, and the IC₅₀ value can be obtained by curvefitting with four parameters (“log(inhibitor) vs. response—Variableslope” mode in GraphPad Prism). The inhibitory activity of compounds ofthe present disclosure on NCI-H358 cell proliferation was provided inTable 2.

TABLE 2 Assay results of compounds of the present disclosure forinhibition of proliferation of KRAS^(G12C)-mutated H358 cells CompoundNCI-H358 IC₅₀ (nM)  1 68.2  2 19.0  4B hydrochloride 27.0  5B 12.9  6A<4.6  8B hydrochloride <4.6  9B 5.5 10 70 11 6.7 12 2.5 13 32.6 15 9.216 1.7 17 0.6 18B 4.7 Conclusion: Some compounds of the presentdisclosure exhibit good inhibitory activity on the proliferation ofNCI-H358 cells.

Assay Example 3: Metabolic Stability of Hepatocytes

Purpose of the assay: Metabolic stabilities of assay compounds inhepatocytes of CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, andhuman were assayed, respectively.

Procedure of the assay: Several 96-well sample precipitation plates wereprepared and named T0, T15, T30, T60, T90, T120, T0-MC, T120-MC andblank substrates, respectively. The recovery medium and incubationmedium were taken out in advance and placed in a 37° C. water bath forpre-heating. Cryopreserved hepatocytes were removed from the liquidnitrogen tank and immediately immersed in a 37° C. water bath(approximately 90 seconds). After the cryopreserved hepatocytes hadthawed and loosened, they were poured into a centrifuge tube containing40 mL of recovery medium, and the tube was gently inverted to allow thecells to be resuspended in the recovery medium. The cells werecentrifuged at 100×g at room temperature for 5 min, and the supernatantwas removed. The hepatocytes were resuspended in an appropriate volumeof incubation medium, and the cell viability was calculated by TrypanBlue staining method. 198 μL of hepatocyte suspension (0.51×10⁶cells/mL) was added to the preheated incubation plate. For the culturemedium control group, 198 μL of hepatocyte-free incubation medium wasadded to T0-MC and T120-MC incubation plate. All incubation plates werepre-incubated in a 37° C. incubator for 10 minutes. Then 2 μL of workingsolutions of the assay sample and the control compound were added,respectively, and the mixture was mixed well. The incubation plate wasimmediately put into the shaker in the incubator, and the reaction wasinitiated while starting the timer. For each time point of eachcompound, 2 duplicate samples were prepared. The incubation conditionswere 37° C., saturated humidity, and 5% CO₂. In the assay system, thefinal concentration of the assay sample was 1 μM, the finalconcentration of the control sample was 3 μM, the final concentration ofhepatocytes was 0.5×10⁶ cells/mL, and the final concentration of thetotal organic solvent was 0.96%, of which the final concentration ofDMSO was 0.1%. At the end of the incubation for the corresponding timepoint, the incubation plate was taken out, and 25 μL of a mixture ofcompound and control compound with cells was added to the sample platecontaining 125 μL of stop solution (200 ng/mL tolbutamide and labetalolin acetonitrile). For the Blank sample plate, 25 μL of hepatocyte-freeincubation medium was added directly. After sealing, all sample plateswere shaken on a shaker at 600 rpm for 10 minutes, and then centrifugedat 3220×g for 20 minutes. Supernatants of the assay sample and thecontrol sample were diluted with ultrapure water at a ratio of 1:3. Allsamples were mixed well and analyzed by LC/MS/MS.

The assay results are shown in Table 3.

TABLE 3 Metabolic stability of the assay compounds in hepatocytes ofCD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and human T_(1/2)CL_(int(hep)) CL_(int(liver)) Compound Species (min) (μL/min/10⁶)(mL/min/kg)  8B CD-1 mice 18.2 76.3 906.0 SD rats 185.2 7.5 35.0Cynomolgus 136.1 10.2 36.7 monkeys Beagle dogs >216.8 <6.4 <44 Human199.5 6.9 19.3 17 CD-1 mice 9.5 146.3 1738.1 SD rats 20.6 67.4 315.2Cynomolgus 27.0 51.3 184.7 monkeys Beagle dogs 182.2 7.6 52.3 Human 99.513.9 38.7 Conclusion: Metabolic assay in hepatocytes of various speciesshowed that the compounds of the present disclosure have good metabolicstability.

Assay Example 4: In Vitro Stability Assay in Liver Microsomes

Purpose of the assay: Metabolic stabilities of the assay compounds inliver microsomes of CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys,and human were assayed, respectively.

Procedure of the assay: Two 96-well incubation plates were prepared andnamed T60 incubation plate and NCF60 incubation plate, respectively. 445μL of microsomal working solutions (liver microsomal proteinconcentration of 0.56 mg/mL) were added to the T60 incubation plate andthe NCF60 incubation plate, respectively, and then the above incubationplates were pre-incubated in a 37° C. water bath for about 10 minutes.

After the pre-incubation, 5 μL of working solutions of the assay sampleor the control compound were added to the T60 incubation plate and theNCF60 incubation plate, respectively, and the mixture was mixed well. 50μL of potassium phosphate buffer was added to each well of the NCF60incubation plate to initiate the reaction. 180 μL of stop solution (200ng/mL tolbutamide and 200 ng/mL labetalol in acetonitrile) and 6 uL ofNADPH regeneration system working solution were added to the T0 stopplate, and 54 μL of sample was transferred from T60 incubation plate toT0 stop plate (generation of T0 sample). The reaction was initiated byadding 44 μL of NADPH regeneration system working solution to each wellof the T60 incubation plate. Only 54 μL of microsome working solution, 6uL of NADPH regeneration system working solution and 180 μL of stopsolution were added to the Blank plate. Therefore, in samples of theassay compound or the control compound, the final reaction concentrationof compound, testosterone, diclofenac and propafenone was 1 μM, theconcentration of liver microsomes was 0.5 mg/mL, and the final reactionconcentrations of DMSO and acetonitrile in the reaction system were0.01% (v/v) and 0.99% (v/v), respectively.

After an appropriate time (e.g., 5, 15, 30, 45 and 60 minutes) ofincubation, 180 μL of stop solutions (200 ng/mL tolbutamide and 200ng/mL labetalol in acetonitrile) were added to the sample wells of eachstop plate, respectively. 60 μL of sample was removed from the T60incubation plate to stop the reaction. All sample plates were shakenwell and then centrifuged at 3220×g for 20 minutes. Then 80 μL ofsupernatant was taken out from each well, and diluted in 240 μL of purewater for liquid chromatography-tandem mass spectrometry analysis. Allsamples were injected and analyzed by liquid chromatography-tandem massspectrometry.

TABLE 4 Metabolic stability of the assay compounds in liver microsomesof CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and humanT_(1/2) CL_(int(hep)) CL_(int(liver)) Compound Species (min)(μL/min/10⁶) (mL/min/kg)  8B CD-1 mice 12.6 110.1 436.1 SD rats >145<9.6 <17.3 Cynomolgus 23.3 59.5 80.3 monkeys Beagle dogs >145 <9.6 <13.8Human 60.3 23.0 20.7 17 CD-1 mice 4.9 284.6 1126.8 SD rats 23.0 60.2108.3 Cynomolgus 6.2 224.6 303.2 monkeys Beagle dogs >145 <9.6 <13.8Human 20.4 67.9 61.1 Conclusion: The assay of the metabolic stability inliver microsomes showed that the compounds of the present disclosurehave good metabolic stability.

Assay Example 5: Stability Assay in Plasma

Purpose of the assay: Stabilities of the assay compounds in plasma ofCD-1 mice and human were assayed, respectively.

Procedure of the assay: Cryopreserved plasma was thawed for 10-20 min.After the plasma was completely thawed, it was placed in a centrifugeand centrifuged at 3220×g for 5 min to remove any suspended matter andsediment in the plasma. 96-well incubation plates were prepared andnamed T0, T10, T30, T60, T120, respectively. 98 μL of blank plasmas ofmouse, rat, canine, monkey and human were added to the correspondingincubation plates, then 2 μL of working solutions of the compound or thecontrol compound were added to the corresponding plates in duplicate.All samples were incubated in a 37° C. water bath. The final incubationconcentrations of the compound and the control compounds bisacodyl,enalapril maleate, procaine and probanthine were 2 μM, and the finalorganic phase content was 2.0%. At the end of incubation for each timepoint, the corresponding incubation plate was removed and 400 μL of asolution of 200 ng/mL of tolbutamide and labetalol in acetonitrile wasadded to each corresponding sample well to precipitate the protein. Allsample plates were sealed and shaken well, and then centrifuged at3220×g for 20 minutes. 50 μL of supernatant was taken out and diluted in100 μL of ultrapure water. All samples were mixed well and then analyzedby LC/MS/MS.

TABLE 5 Stability of the assay compounds in plasma of CD-1 mice andhuman Detection of assay compound Compound Species content within 120min  8B CD-1 mice 110% Human 114% 17 CD-1 mice  94% Human  93%Conclusion: The compounds of the present disclosure have good stabilityin plasma of human and mouse.

Assay Example 6: Stability Assay in Whole Blood

Purpose of the assay: Stabilities of the assay compounds in whole bloodof CD-1 mice, SD rats, Beagle dogs and cynomolgus monkeys were assayed,respectively.

Procedure of the assay: On the day of the assay or the day before theassay, fresh whole blood from CD-1 mice, SD rats, beagle dogs, andcynomolgus monkeys was collected using anticoagulant EDTA-K2. Prior tothe start of the assay, the whole blood was mixed with PBS in 1:1 (v: v)and the mixture was preheated in a 37° C. water bath for 10-20 minutes.96-well incubation plates were prepared and named T0, T30, T60, T240,respectively. In the corresponding incubation plates, including T0, T30,T60 and T240 incubation plates, 2 μL of working solutions of thecompound or the control compound were mixed with 98 μL of blank wholeblood of mice, rats, canines, monkeys and human in duplicate. Allsamples were incubated in a 37° C. water bath. The final incubationconcentration of the compound was 5 μM and the final incubationconcentration of the control compound was 2 μM. At the end of incubationfor each time point, the corresponding incubation plate was removed and100 μL of ultrapure water was immediately added to the correspondingsample wells, and mixed well. 800 μL of a solution of 200 ng/mLtolbutamide and labetalol in acetonitrile was added to precipitate theprotein. The sample plates were sealed and shaken well, and thencentrifuged at 3220×g for 20 min. 150 μL of supernatant was taken outand analyzed by LC/MS/MS.

TABLE 6 Stability of the assay compounds in the whole blood of CD-1mice, SD rats, beagle dogs, and cynomolgus monkeys Detection of assaycompound Compound Species content within 120 min  8B CD-1 mice 100% SDrats 104% Cynomolgus monkeys  58% Beagle dogs  96% 17 CD-1 mice 117% SDrats 115% Cynomolgus monkeys  77% Beagle dogs 102% Conclusion: Thestability assay in the whole blood of various species showed that thecompounds of the present disclosure have good stability in whole blood.

Assay Example 7: Assay of Protein Binding Rate

Purpose of the assay: Protein binding rate of the assay compounds inplasma of CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and humanwas determined by equilibrium dialysis.

Procedure of the assay: Plasma samples with a compound concentration of2 μM were prepared using plasma of the above five species, placed in a96-well equilibrium dialysis device, and dialyzed with phosphate buffersolution at 37±1° C. for 4 hours. Warfarin was used as the controlcompound in this assay. The concentrations of the assay compounds inplasma and dialysis buffer were determined by LC-MS/MS method.

TABLE 7 Protein binding rate of the assay compounds in CD-1 mice, SDrats, beagle dogs, cynomolgus monkeys, and human Compound SpeciesProtein unbound rate  8B CD-1 mice 12.0 SD rats 9.8 Cynomolgus monkeys23.9 Beagle dogs 6.0 Human 10.6 17 CD-1 mice 1.5 SD rats 4.8 Cynomolgusmonkeys 7.8 Beagle dogs 3.3 Human 4.8 Conclusion: Assay on plasmabinding rates of various species showed that the compounds of thepresent disclosure have higher protein unbound rate in plasma.

Assay Example 8: Assay on Pharmacokinetics In Vivo

1) Assay on the Pharmacokinetics of the Assay Compounds by OralAdministration and Intravenous Injection in SD Rats

The assay compound was mixed with 5% dimethyl sulfoxide/95% (10%hydroxypropyl-β-cyclodextrin) solution. The mixture was vortexed andsonicated to prepare a 1 mg/mL clear solution, which was filteredthrough a microporous membrane for later use. Male SD rats aged 7 to 10weeks were selected, and administered candidate compound solutionsintravenously or orally. Whole blood was collected for a certain periodof time, and prepared to obtain plasma. Drug concentration was analyzedby LC-MS/MS method, and pharmacokinetic parameters were calculated byPhoenix WinNonlin software (Pharsight, USA). The results of the assayare shown in Table 8:

TABLE 8 Pharmacokinetic results of the assay compounds Route of CompoundCompound administration Pharmacokinetic parameters 8B 17 Plasma proteinunbound rate PPB 9.8 4.8 (Unbound %) Intravenous Dose (mg/kg) 2.0 2.0injection Half-life period, T_(1/2) (h) 2.8 1.9 administration Clearancerate, CL (ml/min/kg) 85.2  71.5  Apparent volume of distribution,17.9/203  10.6/221  Vd_(ss)/Vd_(ss), u(L/kg) AUC_(0-last)/AUC_(u) (nM ·h) 544/53.3 653/31.3 Oral Dose (mg/kg) 9.7 9.8 administrationTime-to-peak, T_(max) (h) 1.5 1.5 Peak concentration, C_(max)/C_(max, u)(nM) 218/21.3 220/10.6 AUC_(0-last)/AUC_(u) (nM · h) 1211/119  995/47.8Bioavailability F (%)  44.5%  30.5% Note: Vd_(ss), u is the apparentvolume of distribution under unbound plasma protein (Vd_(ss), u =Vd_(ss)/PPB(Unbound %)); C_(max, u), and AUC_(0-last, u) are thecorresponding values under unbound plasma protein (C_(max, u) = C_(max)× PPB(Unbound %); AUC_(0-last, u) = AUC_(0-last) × PPB(Unbound %))Conclusion: PK assay showed that the compounds of the present disclosurehave higher unbound plasma exposure and good oral bioavailability inrats.

2) Assay on the Pharmacokinetics of the Assay Compounds by OralAdministration and Intravenous Injection in CD Mice

The assay compound was mixed with 5% dimethyl sulfoxide/95% (10%hydroxypropyl-β-cyclodextrin) solution. The mixture was vortexed andsonicated to prepare a 1 mg/mL clear solution, which was filteredthrough a microporous membrane for later use. Male CD mice aged 7 to 10weeks were selected, and administered candidate compound solutionsintravenously or orally. Whole blood was collected for a certain periodof time, and prepared to obtain plasma. Drug concentration was analyzedby LC-MS/MS method, and pharmacokinetic parameters were calculated byPhoenix WinNonlin software (Pharsight, USA). The results of the assayare shown in Table 9:

TABLE 9 Pharmacokinetic results of the assay compounds Route of CompoundCompound administration Pharmacokinetic parameters 8B 17 Plasma proteinunbound rate PPB 1.54 12.0 (Unbound %) Intravenous Dose (mg/kg) 2.39 2.0injection Half-life period, T_(1/2) (h) 1.0 1.7 administration Clearancerate, CL (ml/min/kg) 37.3 40.6 Apparent volume of distribution,  2.6/168.8  3.9/32.3 Vd_(ss)/Vd_(ss), u(L/kg) AUC_(0-last)/AUC_(u) (nM· h) 1311/20.2  1297/155.6 Oral Dose (mg/kg) 14.7 10.3 administrationTime-to-peak, T_(max) (h) 0.25 1.0 Peak concentration,C_(max)/C_(max, u) (nM) 1460/22.5 431/51.7 AUC_(0-last)/AUC_(u) (nM · h)2403/37.0 1422/170.6 Bioavailability F (%) 24.4% 21.9% Note: Vd_(ss), uis the apparent volume of distribution under unbound plasma protein(Vd_(ss), u = Vd_(ss)/PPB(Unbound %)); C_(max, u), and AUC_(0-last, u),are the corresponding values under unbound plasma protein (C_(max, u) =C_(max) × PPB(Unbound %); AUC_(0-last, u) = AUC_(0-last) × PPB(Unbound%)) Conclusion: PK assay showed that the compounds of the presentdisclosure have higher unbound plasma exposure and good oralbioavailability in mice.

Assay Example 9: Assay on Pharmacodynamics In Vivo

Assay on Pharmacodynamics In Vivo in a Subcutaneously Transplanted TumorModel of Human Pancreatic Cancer Mia PaCa-2 Cells in Balb/c Nude Mice

1. Cell Culture and Tumor Tissue Preparation

Cell culture: Human pancreatic cancer Mia PaCa-2 cells (ATCC-CRL-1420)were cultured in monolayer in vitro in DMEM medium with 10% fetal calfserum and 2.5% horse serum in a 37° C., 5% carbon dioxide incubator.Cells were passaged by routine digestion with trypsin-EDTA twice a week.When the cell saturation reached 80%-90% and the cell number met therequirement, the cells were harvested, counted, and resuspended in anappropriate amount of PBS. Matrigel was added in a ratio of 1:1 toobtain a cell suspension with a cell density of 25×10⁶ cells/mL.

Cell inoculation: 0.2 mL (5×10⁶ cells/mouse) of Mia PaCa-2 cells (plusMatrigel, 1:1 by volume) were subcutaneously inoculated into the rightback of each mouse. When the average tumor volume reached 190 mm³, micewere randomized into groups based on tumor volume and administration wasinitiated according to the protocol in Table 10.

TABLE 10 Assay animal grouping and administration protocol Num- Adminis-Route Adminis- ber Dosage tration of tration of Com- (mg/ volumeadminis- fre- Group animals pound kg) (μL/g) tration quency 1 6 Vehicle— 10 PO QD x22 2 6 8B 10 10 PO QD x22 3 6 8B 30 10 PO QD x22 4 6 17 1010 PO QD x22 5 6 17 30 10 PO QD x22 Note: PO indicates oraladministration; QD indicates once daily.

2. Tumor Measurements and Assay Indicators

Tumor diameter was measured with vernier caliper twice a week. Thecalculation formula of tumor volume was: V=0.5a×b², where a and brepresent the long and short diameters of the tumor, respectively.

The anti-tumor efficacy of compounds was evaluated by TGI (%) orrelative tumor proliferation rate T/C (%). Relative tumor proliferationrate T/C (%)=TRTV/CRTV×100% (TRTV: RTV in a treatment group; CRTV: RTVin a negative control group). The relative tumor volume (RTV) wascalculated according to results of tumor measurement, and thecalculation formula was RTV=Vt/V0, where V0 was average tumor volumemeasured at the time of administration by group (i.e., D0), and Vt wasaverage tumor volume at the time of a certain measurement. For TRTV andCRTV, data on the same day were used.

TGI (%) reflected tumor growth inhibition rate. TGI (%)=[(1−(averagetumor volume at the end of administration of a treatment group−averagetumor volume at the beginning of administration of the treatmentgroup))/(average tumor volume at the end of treatment of a vehiclecontrol group−average tumor volume at the beginning of treatment of thevehicle control group)]×100%.

3. Results of the Assay

The assay results are shown in FIGS. 1 and 2 .

The results at 22 days of administration are shown in Table 11.

TABLE 11 T/C and TGI on day 22 of administration Compound Dosage Averagetumor volume T/C TGI Vehicle N/A 2016.29 mm³  N/A N/A  8B 10 mg/kg745.84 mm³ 36.99% 66.89%  8B 30 mg/kg 227.15 mm³ 11.28% 94.23% 17 10mg/kg 249.87 mm³ 12.39% 93.06% 17 30 mg/kg 124.14 mm³ 6.16% 99.64%Conclusion: The compounds of the present disclosure have significanttumor-inhibiting effect. Moreover, the body weight of mice in each dosegroup is stable, and there is no obvious intolerance.

1. A compound represented by formula (III) or a pharmaceuticallyacceptable salt thereof,

wherein T₁ is selected from O and N; R₁ is selected from C₆₋₁₀ aryl and5- to 10-membered heteroaryl, wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5R_(a); when T₁ is O, R₂ is not present; when T₁ is N, R₂ is selectedfrom H, C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and —S(═O)₂—C₁₋₃ alkyl, whereinthe C₁₋₃ alkyl, —C(═O)—C₁₋₃ alkyl and —S(═O)₂—C₁₋₃ alkyl are optionallysubstituted with 1, 2 or 3 R_(b); R₃ is C₁₋₃ alkyl, wherein the C₁₋₃alkyl is optionally substituted with 1, 2 or 3 R_(c); R₄ is selectedfrom H and C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substitutedwith 1, 2 or 3 R_(d); R₅, R₆ and R₇ are each independently selected fromH, F, Cl, Br, I, and C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionallysubstituted with 1, 2 or 3 F; R₈ is selected from H and CH₃; R_(a) iseach independently selected from F, Cl, Br, I, OH, NH₂, CN, C₁₋₃ alkyl,C₁₋₃ alkoxy, C2-3 alkynyl and C₂₋₃ alkenyl, wherein the C₁₋₃ alkyl, C₁₋₃alkoxy, C₂₋₃ alkynyl and C₂₋₃ alkenyl are optionally substituted with 1,2 or 3 F; R_(b) is each independently selected from F, Cl, Br, I, OH andNH₂; R_(c) is each independently selected from 4- to 8-memberedheterocycloalkyl, wherein the 4- to 8-membered heterocycloalkyl isoptionally substituted with 1, 2 or 3 R; R_(d) is each independentlyselected from F, Cl, Br, I, OH, NH₂ and CN; R is each independentlyselected from H, F, Cl, Br, OH, CN, C₁₋₃ alkyl, C₁₋₃ alkoxy and —C₁₋₃alkyl-O—C(═O)—C₁₋₃ alkylamino; provided that when R₁ is naphthyl, thenaphthyl is optionally substituted with F, Cl, Br, OH, NH₂, CF₃, CH₂CH₃and —C≡CH, and R₅, R₆ and R₇ are each independently H.
 2. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein R_(a) is each independently selected from F, Cl, Br, I, OH, NH₂,CN, CH₃, CH₂CH₃, OCH₃, OCH₂CH₃, —CH═CH₂, —CH₂—CH═CH₂ and —C≡CH, whereinthe CH₃, CH₂CH₃, OCH₃, OCH₂CH₃, —CH═CH₂, —CH₂—CH═CH₂ and —C≡CH areoptionally substituted with 1, 2 or 3F; alternatively, wherein R_(a) iseach independently selected from F, OH, NH₂, CH₃, CF₃, CH₂CH₃ and —C≡CH.3. (canceled)
 4. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R₁ is selected fromphenyl, naphthyl, indolyl and indazolyl, wherein the phenyl, naphthyl,indolyl and indazolyl are optionally substituted with 1, 2 or 3 R_(a).5. The compound according to claim 4, or a pharmaceutically acceptablesalt thereof, wherein R₁ is selected from and


6. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R₂ is selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂,wherein the CH₃, CH₂CH₃ and CH(CH₃)₂ are optionally substituted with 1,2 or 3 R_(b); alternatively, wherein R₂ is selected from H and CH₃. 7.(canceled)
 8. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R is each independently selected fromH, F, Cl, Br, OH, CN, CH₃, CH₂CH₃, CH₂CF₃, OCH₃, OCF₃ and


9. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R_(c) is selected from tetrahydropyrrolyl andhexahydro-1H-pyrrolizinyl, wherein the tetrahydropyrrolyl andhexahydro-1H-pyrrolizinyl are optionally substituted with 1, 2 or 3 R;alternatively, wherein R_(c) is selected from


10. (canceled)
 11. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R_(c) is selected from


12. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R₃ is CH₃, wherein the CH₃ is optionallysubstituted with 1, 2 or 3 R_(c).
 13. The compound according to claim12, or a pharmaceutically acceptable salt thereof, wherein R₃ isselected from


14. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R₃ is selected from


15. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R₄ is selected from H and CH₃, wherein the CH₃ isoptionally substituted with 1, 2 or 3 R_(d); alternatively, wherein R₄is selected from H, CH₃ and CH₂CN.
 16. (canceled)
 17. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound is selected from

wherein R₁ is as defined claim 1; R₄ is C₁₋₃ alkyl, wherein the C₁₋₃alkyl is optionally substituted with 1, 2 or 3 R_(d); R_(d) is eachindependently selected from F, Cl, Br, I, OH, NH₂ and CN; R₅ is asdefined in claim 1; R_(c) is as defined in claim 1; the carbon atom with“*” is a chiral carbon atom, which exists in the form of (R) or (S)single enantiomer or is enriched in one enantiomer.
 18. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound is selected from

wherein R₁, R₂, R₄, R₅, R₆, R₇, R₈ and R are defined in claim
 1. 19. Acompound represented by the following formula, or a pharmaceuticallyacceptable salt thereof,

alternatively, wherein the compound is selected from

alternatively, wherein the compound is selected from


20. (canceled)
 21. (canceled)
 22. A pharmaceutical composition,comprising the compound according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 23. A compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein the compound isselected from

wherein R₁ is

R₄ is CH₂CN, which exists in the form of (S) single enantiomer or isenriched in (S) enantiomer; R₅ is selected from H, F, Cl, Br, I, andC₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally substituted with 1, 2or 3 F; R_(c) is selected from

 alternatively, is selected from


24. A compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein the compound is selected from

wherein R₄ is selected from H, CH₃ and CH₂CN, which exists in the formof (R) single enantiomer or is enriched in (R) enantiomer; R₈ isselected from H and CH₃, which exists in the form of (S) singleenantiomer or is enriched in (S) enantiomer; R₅ is selected from H, F,Cl, Br, I, and C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionallysubstituted with 1, 2 or 3 F; and R is selected from H, F, Cl, Br, andC₁₋₃ alkyl.
 25. A compound according to claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 26. A compound accordingto claim 1, which is:

or a pharmaceutically acceptable salt thereof.